The human endocannabinoid system (ECS) is a complex signalling network involved in many key physiological processes. The ECS includes the cannabinoid receptors, the endocannabinoid ligands, and the enzymes related to their synthesis and degradation. Other cannabinoids encompass the phytocannabinoids from Cannabis sativa L.(marijuana) and the synthetic cannabinoids. Alterations in the ECS are associated with different diseases, including inflammatory and immune-mediated disorders such as allergy. Allergy is a global health problem of increasing prevalence with high socio-economic impact. Different studies have convincingly demonstrated that cannabinoids play a role in allergy, but their actual contribution is still controversial. It has been shown that cannabinoids exert anti-inflammatory properties in the airways and the skin of allergic patients. Other studies reported that cannabinoids might exacerbate asthma and atopic dermatitis mainly depending on CB2-mediated signalling pathways. A better understanding of the molecular mechanisms involved in the mode of action of specific cannabinoids and cannabinoid receptors on relevant immune cells under different biological contexts might well contribute to the design of novel strategies for the prevention and treatment of allergic diseases. Future research in this promising emerging field in the context of allergy is warranted for the upcoming years.

1.
Gaoni
Y
,
Mechoulam
R
.
Isolation, structure and partial synthesis of an active constituent of hashish
.
J Am Chem Soc
.
1964
;
86
(
8
):
1646
7
.0002-7863
2.
Matsuda
LA
,
Lolait
SJ
,
Brownstein
MJ
,
Young
AC
,
Bonner
TI
.
Structure of a cannabinoid receptor and functional expression of the cloned cDNA
.
Nature
.
1990
Aug
;
346
(
6284
):
561
4
.
[PubMed]
0028-0836
3.
Munro
S
,
Thomas
KL
,
Abu-Shaar
M
.
Molecular characterization of a peripheral receptor for cannabinoids
.
Nature
.
1993
Sep
;
365
(
6441
):
61
5
.
[PubMed]
0028-0836
4.
Lu
HC
,
Mackie
K
.
An Introduction to the Endogenous Cannabinoid System
.
Biol Psychiatry
.
2016
Apr
;
79
(
7
):
516
25
.
[PubMed]
1873-2402
5.
Di Marzo
V
.
New approaches and challenges to targeting the endocannabinoid system
.
Nat Rev Drug Discov
.
2018
Sep
;
17
(
9
):
623
39
.
[PubMed]
1474-1784
6.
Velasco
G
,
Sánchez
C
,
Guzmán
M
.
Towards the use of cannabinoids as antitumour agents
.
Nat Rev Cancer
.
2012
May
;
12
(
6
):
436
44
.
[PubMed]
1474-1768
7.
Klein
TW
.
Cannabinoid-based drugs as anti-inflammatory therapeutics
.
Nat Rev Immunol
.
2005
May
;
5
(
5
):
400
11
.
[PubMed]
1474-1733
8.
Akdis
CA
,
Arkwright
PD
,
Brüggen
MC
,
Busse
W
,
Gadina
M
,
Guttman-Yassky
E
, et al.
Type 2 immunity in the skin and lungs
.
Allergy
.
2020
Apr
.
[PubMed]
1398-9995
9.
Palomares
O
,
Akdis
M
,
Martín-Fontecha
M
,
Akdis
CA
.
Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells
.
Immunol Rev
.
2017
Jul
;
278
(
1
):
219
36
.
[PubMed]
1600-065X
10.
Agache
I
,
Annesi-Maesano
I
,
Bonertz
A
,
Branca
F
,
Cant
A
,
Fras
Z
, et al.
Prioritizing research challenges and funding for allergy and asthma and the need for translational research-The European Strategic Forum on Allergic Diseases
.
Allergy
.
2019
Nov
;
74
(
11
):
2064
76
.
[PubMed]
1398-9995
11.
Verschoor
D
,
von Gunten
S
.
Allergy and Atopic Diseases: An Update on Experimental Evidence
.
Int Arch Allergy Immunol
.
2019
;
180
(
4
):
235
43
.
[PubMed]
1423-0097
12.
Senti
G
,
Freiburghaus
AU
,
Larenas-Linnemann
D
,
Hoffmann
HJ
,
Patterson
AM
,
Klimek
L
, et al.
Intralymphatic Immunotherapy: Update and Unmet Needs
.
Int Arch Allergy Immunol
.
2019
;
178
(
2
):
141
9
.
[PubMed]
1423-0097
13.
Bonertz
A
,
Roberts
GC
,
Hoefnagel
M
,
Timon
M
,
Slater
JE
,
Rabin
RL
, et al.
Challenges in the implementation of EAACI guidelines on allergen immunotherapy: A global perspective on the regulation of allergen products
.
Allergy
.
2018
Jan
;
73
(
1
):
64
76
.
[PubMed]
1398-9995
14.
Braun
A
,
Engel
T
,
Aguilar-Pimentel
JA
,
Zimmer
A
,
Jakob
T
,
Behrendt
H
, et al.
Beneficial effects of cannabinoids (CB) in a murine model of allergen-induced airway inflammation: role of CB1/CB2 receptors
.
Immunobiology
.
2011
Apr
;
216
(
4
):
466
76
.
[PubMed]
1878-3279
15.
Gaffal
E
,
Cron
M
,
Glodde
N
,
Tüting
T
.
Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors
.
Allergy
.
2013
Aug
;
68
(
8
):
994
1000
.
[PubMed]
1398-9995
16.
Frei
RB
,
Luschnig
P
,
Parzmair
GP
,
Peinhaupt
M
,
Schranz
S
,
Fauland
A
, et al.
Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen-induced pulmonary inflammation in mice
.
Allergy
.
2016
Jul
;
71
(
7
):
944
56
.
[PubMed]
1398-9995
17.
Mimura
T
,
Ueda
Y
,
Watanabe
Y
,
Sugiura
T
.
The cannabinoid receptor-2 is involved in allergic inflammation
.
Life Sci
.
2012
Jun
;
90
(
21-22
):
862
6
.
[PubMed]
1879-0631
18.
Pandey
R
,
Mousawy
K
,
Nagarkatti
M
,
Nagarkatti
P
.
Endocannabinoids and immune regulation
.
Pharmacol Res
.
2009
Aug
;
60
(
2
):
85
92
.
[PubMed]
1096-1186
19.
Fernández-Ruiz
J
.
The biomedical challenge of neurodegenerative disorders: an opportunity for cannabinoid-based therapies to improve on the poor current therapeutic outcomes
.
Br J Pharmacol
.
2019
May
;
176
(
10
):
1370
83
.
[PubMed]
1476-5381
20.
Toczek
M
,
Malinowska
B
.
Enhanced endocannabinoid tone as a potential target of pharmacotherapy
.
Life Sci
.
2018
Jul
;
204
:
20
45
.
[PubMed]
1879-0631
21.
Pertwee
RG
.
Endocannabinoids and Their Pharmacological Actions
.
Handb Exp Pharmacol
.
2015
;
231
:
1
37
.
[PubMed]
0171-2004
22.
De Petrocellis
L
,
Di Marzo
V
.
Non-CB1, non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels
.
J Neuroimmune Pharmacol
.
2010
Mar
;
5
(
1
):
103
21
.
[PubMed]
1557-1904
23.
Maccarrone
M
,
Bab
I
,
Bíró
T
,
Cabral
GA
,
Dey
SK
,
Di Marzo
V
, et al.
Endocannabinoid signaling at the periphery: 50 years after THC
.
Trends Pharmacol Sci
.
2015
May
;
36
(
5
):
277
96
.
[PubMed]
1873-3735
24.
Pisanti
S
,
Malfitano
AM
,
Ciaglia
E
,
Lamberti
A
,
Ranieri
R
,
Cuomo
G
, et al.
Cannabidiol: state of the art and new challenges for therapeutic applications
.
Pharmacol Ther
.
2017
Jul
;
175
:
133
50
.
[PubMed]
1879-016X
25.
Hourani
W
,
Alexander
SP
.
Cannabinoid ligands, receptors and enzymes: pharmacological tools and therapeutic potential
.
Brain Neurosci Adv
.
2018
Jun
;
2
:
2398212818783908
.
[PubMed]
2398-2128
26.
Pertwee
RG
.
The pharmacology of cannabinoid receptors and their ligands: an overview
.
Int J Obes (Lond)
.
2006
Apr
;
30
Suppl 1
:
S13
8
.
[PubMed]
0307-0565
27.
Maccarrone
M
,
Dainese
E
,
Oddi
S
.
Intracellular trafficking of anandamide: new concepts for signaling
.
Trends Biochem Sci
.
2010
Nov
;
35
(
11
):
601
8
.
[PubMed]
0968-0004
28.
Maccarrone
M
.
Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years
.
Front Mol Neurosci
.
2017
May
;
10
:
166
.
[PubMed]
1662-5099
29.
Chicca
A
,
Marazzi
J
,
Nicolussi
S
,
Gertsch
J
.
Evidence for bidirectional endocannabinoid transport across cell membranes
.
J Biol Chem
.
2012
Oct
;
287
(
41
):
34660
82
.
[PubMed]
1083-351X
30.
Deng
H
,
Li
W
.
Monoacylglycerol lipase inhibitors: modulators for lipid metabolism in cancer malignancy, neurological and metabolic disorders
.
Acta Pharm Sin B
.
2020
Apr
;
10
(
4
):
582
602
.
[PubMed]
2211-3835
31.
Celorrio
M
,
Fernández-Suárez
D
,
Rojo-Bustamante
E
,
Echeverry-Alzate
V
,
Ramírez
MJ
,
Hillard
CJ
, et al.
Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease
.
Brain Behav Immun
.
2016
Oct
;
57
:
94
105
.
[PubMed]
1090-2139
32.
Gil-Ordóñez
A
,
Martín-Fontecha
M
,
Ortega-Gutiérrez
S
,
López-Rodríguez
ML
.
Monoacylglycerol lipase (MAGL) as a promising therapeutic target
.
Biochem Pharmacol
.
2018
Nov
;
157
:
18
32
.
[PubMed]
1873-2968
33.
Hua
T
,
Vemuri
K
,
Pu
M
,
Qu
L
,
Han
GW
,
Wu
Y
, et al.
Crystal Structure of the Human Cannabinoid Receptor CB1.
Cell.
2016
;167(3):750-62 e14.
34.
Shao
Z
,
Yin
J
,
Chapman
K
,
Grzemska
M
,
Clark
L
,
Wang
J
, et al.
High-resolution crystal structure of the human CB1 cannabinoid receptor
.
Nature
.
2016
Dec
;
540
(
7634
):
602
6
.
[PubMed]
1476-4687
35.
Li
X
,
Hua
T
,
Vemuri
K
,
Ho
JH
,
Wu
Y
,
Wu
L
, et al.
Crystal Structure of the Human Cannabinoid Receptor CB2.
Cell.
2019
;176(3):459-67 e13.
36.
Bonhaus
DW
,
Chang
LK
,
Kwan
J
,
Martin
GR
.
Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses
.
J Pharmacol Exp Ther
.
1998
Dec
;
287
(
3
):
884
8
.
[PubMed]
0022-3565
37.
Galve-Roperh
I
,
Chiurchiù
V
,
Díaz-Alonso
J
,
Bari
M
,
Guzmán
M
,
Maccarrone
M
.
Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation
.
Prog Lipid Res
.
2013
Oct
;
52
(
4
):
633
50
.
[PubMed]
1873-2194
38.
Maccarrone
M
,
Guzmán
M
,
Mackie
K
,
Doherty
P
,
Harkany
T
.
Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies
.
Nat Rev Neurosci
.
2014
Dec
;
15
(
12
):
786
801
.
[PubMed]
1471-0048
39.
Liu
QR
,
Pan
CH
,
Hishimoto
A
,
Li
CY
,
Xi
ZX
,
Llorente-Berzal
A
, et al.
Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands
.
Genes Brain Behav
.
2009
Jul
;
8
(
5
):
519
30
.
[PubMed]
1601-183X
40.
Van Sickle
MD
,
Duncan
M
,
Kingsley
PJ
,
Mouihate
A
,
Urbani
P
,
Mackie
K
, et al.
Identification and functional characterization of brainstem cannabinoid CB2 receptors
.
Science
.
2005
Oct
;
310
(
5746
):
329
32
.
[PubMed]
1095-9203
41.
Massa
F
,
Marsicano
G
,
Hermann
H
,
Cannich
A
,
Monory
K
,
Cravatt
BF
, et al.
The endogenous cannabinoid system protects against colonic inflammation
.
J Clin Invest
.
2004
Apr
;
113
(
8
):
1202
9
.
[PubMed]
0021-9738
42.
Romano
B
,
Borrelli
F
,
Fasolino
I
,
Capasso
R
,
Piscitelli
F
,
Cascio
M
, et al.
The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis
.
Br J Pharmacol
.
2013
May
;
169
(
1
):
213
29
.
[PubMed]
1476-5381
43.
Martin-Fontecha
M
,
Eiwegger
T
,
Jartti
T
,
Rueda-Zubiaurre
A
,
Tiringer
K
,
Stepanow
J
, et al.
The expression of cannabinoid receptor 1 is significantly increased in atopic patients. J Allergy Clin Immunol.
2014
;133(3):926-9 e2.
44.
Maresz
K
,
Carrier
EJ
,
Ponomarev
ED
,
Hillard
CJ
,
Dittel
BN
.
Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli
.
J Neurochem
.
2005
Oct
;
95
(
2
):
437
45
.
[PubMed]
0022-3042
45.
Patel
KD
,
Davison
JS
,
Pittman
QJ
,
Sharkey
KA
.
Cannabinoid CB(2) receptors in health and disease
.
Curr Med Chem
.
2010
;
17
(
14
):
1393
410
.
[PubMed]
1875-533X
46.
Sawzdargo
M
,
Nguyen
T
,
Lee
DK
,
Lynch
KR
,
Cheng
R
,
Heng
HH
, et al.
Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain
.
Brain Res Mol Brain Res
.
1999
Feb
;
64
(
2
):
193
8
.
[PubMed]
0169-328X
47.
Ryberg
E
,
Larsson
N
,
Sjögren
S
,
Hjorth
S
,
Hermansson
NO
,
Leonova
J
, et al.
The orphan receptor GPR55 is a novel cannabinoid receptor
.
Br J Pharmacol
.
2007
Dec
;
152
(
7
):
1092
101
.
[PubMed]
0007-1188
48.
Ross
RA
.
The enigmatic pharmacology of GPR55
.
Trends Pharmacol Sci
.
2009
Mar
;
30
(
3
):
156
63
.
[PubMed]
0165-6147
49.
Chiurchiù
V
,
Lanuti
M
,
De Bardi
M
,
Battistini
L
,
Maccarrone
M
.
The differential characterization of GPR55 receptor in human peripheral blood reveals a distinctive expression in monocytes and NK cells and a proinflammatory role in these innate cells
.
Int Immunol
.
2015
Mar
;
27
(
3
):
153
60
.
[PubMed]
1460-2377
50.
Stančić
A
,
Jandl
K
,
Hasenöhrl
C
,
Reichmann
F
,
Marsche
G
,
Schuligoi
R
, et al.
The GPR55 antagonist CID16020046 protects against intestinal inflammation
.
Neurogastroenterol Motil
.
2015
Oct
;
27
(
10
):
1432
45
.
[PubMed]
1365-2982
51.
Sharir
H
,
Console-Bram
L
,
Mundy
C
,
Popoff
SN
,
Kapur
A
,
Abood
ME
.
The endocannabinoids anandamide and virodhamine modulate the activity of the candidate cannabinoid receptor GPR55
.
J Neuroimmune Pharmacol
.
2012
Dec
;
7
(
4
):
856
65
.
[PubMed]
1557-1904
52.
Muller
C
,
Morales
P
,
Reggio
PH
.
Cannabinoid Ligands Targeting TRP Channels
.
Front Mol Neurosci
.
2019
Jan
;
11
:
487
.
[PubMed]
1662-5099
53.
Storozhuk
MV
,
Zholos
AV
.
TRP Channels as Novel Targets for Endogenous Ligands: Focus on Endocannabinoids and Nociceptive Signalling
.
Curr Neuropharmacol
.
2018
Jan
;
16
(
2
):
137
50
.
[PubMed]
1875-6190
54.
De Petrocellis
L
,
Ligresti
A
,
Moriello
AS
,
Allarà
M
,
Bisogno
T
,
Petrosino
S
, et al.
Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes
.
Br J Pharmacol
.
2011
Aug
;
163
(
7
):
1479
94
.
[PubMed]
1476-5381
55.
O’Sullivan
SE
.
An update on PPAR activation by cannabinoids
.
Br J Pharmacol
.
2016
Jun
;
173
(
12
):
1899
910
.
[PubMed]
1476-5381
56.
O’Sullivan
SE
,
Kendall
DA
.
Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease
.
Immunobiology
.
2010
Aug
;
215
(
8
):
611
6
.
[PubMed]
1878-3279
57.
Menendez-Gutierrez
MP
,
Roszer
T
,
Ricote
M
.
Biology and therapeutic applications of peroxisome proliferator- activated receptors
.
Curr Top Med Chem
.
2012
;
12
(
6
):
548
84
.
[PubMed]
1873-4294
58.
Hegde
VL
,
Singh
UP
,
Nagarkatti
PS
,
Nagarkatti
M
.
Critical Role of Mast Cells and Peroxisome Proliferator-Activated Receptor γ in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo
.
J Immunol
.
2015
Jun
;
194
(
11
):
5211
22
.
[PubMed]
1550-6606
59.
Fakhfouri
G
,
Ahmadiani
A
,
Rahimian
R
,
Grolla
AA
,
Moradi
F
,
Haeri
A
.
WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway
.
Neuropharmacology
.
2012
Sep
;
63
(
4
):
653
66
.
[PubMed]
1873-7064
60.
Chiurchiù
V
,
Battistini
L
,
Maccarrone
M
.
Endocannabinoid signalling in innate and adaptive immunity
.
Immunology
.
2015
Mar
;
144
(
3
):
352
64
.
[PubMed]
1365-2567
61.
Correa
F
,
Docagne
F
,
Clemente
D
,
Mestre
L
,
Becker
C
,
Guaza
C
.
Anandamide inhibits IL-12p40 production by acting on the promoter repressor element GA-12: possible involvement of the COX-2 metabolite prostamide E(2)
.
Biochem J
.
2008
Feb
;
409
(
3
):
761
70
.
[PubMed]
1470-8728
62.
Fitzpatrick
JM
,
Minogue
E
,
Curham
L
,
Tyrrell
H
,
Gavigan
P
,
Hind
W
, et al.
MyD88-dependent and -independent signalling via TLR3 and TLR4 are differentially modulated by Δ9-tetrahydrocannabinol and cannabidiol in human macrophages
.
J Neuroimmunol
.
2020
Jun
;
343
:
577217
.
[PubMed]
1872-8421
63.
Chiurchiù
V
,
Rapino
C
,
Talamonti
E
,
Leuti
A
,
Lanuti
M
,
Gueniche
A
, et al.
Anandamide Suppresses Proinflammatory T Cell Responses In Vitro through Type-1 Cannabinoid Receptor-Mediated mTOR Inhibition in Human Keratinocytes
.
J Immunol
.
2016
Nov
;
197
(
9
):
3545
53
.
[PubMed]
1550-6606
64.
Matias
I
,
Pochard
P
,
Orlando
P
,
Salzet
M
,
Pestel
J
,
Di Marzo
V
.
Presence and regulation of the endocannabinoid system in human dendritic cells
.
Eur J Biochem
.
2002
Aug
;
269
(
15
):
3771
8
.
[PubMed]
0014-2956
65.
Chiurchiù
V
,
Cencioni
MT
,
Bisicchia
E
,
De Bardi
M
,
Gasperini
C
,
Borsellino
G
, et al.
Distinct modulation of human myeloid and plasmacytoid dendritic cells by anandamide in multiple sclerosis
.
Ann Neurol
.
2013
May
;
73
(
5
):
626
36
.
[PubMed]
1531-8249
66.
Henriquez
JE
,
Crawford
RB
,
Kaminski
NE
.
Suppression of CpG-ODN-mediated IFNα and TNFα response in human plasmacytoid dendritic cells (pDC) by cannabinoid receptor 2 (CB2)-specific agonists
.
Toxicol Appl Pharmacol
.
2019
Apr
;
369
:
82
9
.
[PubMed]
1096-0333
67.
Karmaus
PW
,
Chen
W
,
Crawford
R
,
Kaplan
BL
,
Kaminski
NE
.
Δ9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2
.
Toxicol Sci
.
2013
Feb
;
131
(
2
):
419
33
.
[PubMed]
1096-0929
68.
Do
Y
,
McKallip
RJ
,
Nagarkatti
M
,
Nagarkatti
PS
.
Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation
.
J Immunol
.
2004
Aug
;
173
(
4
):
2373
82
.
[PubMed]
0022-1767
69.
Kapellos
TS
,
Taylor
L
,
Feuerborn
A
,
Valaris
S
,
Hussain
MT
,
Rainger
GE
, et al.
Cannabinoid receptor 2 deficiency exacerbates inflammation and neutrophil recruitment
.
FASEB J
.
2019
May
;
33
(
5
):
6154
67
.
[PubMed]
1530-6860
70.
Zhou
X
,
Yang
L
,
Fan
X
,
Zhao
X
,
Chang
N
,
Yang
L
, et al.
Neutrophil Chemotaxis and NETosis in Murine Chronic Liver Injury via Cannabinoid Receptor 1/ Gαi/o/ ROS/ p38 MAPK Signaling Pathway
.
Cells
.
2020
Feb
;
9
(
2
):
E373
.
[PubMed]
2073-4409
71.
Chouinard
F
,
Turcotte
C
,
Guan
X
,
Larose
MC
,
Poirier
S
,
Bouchard
L
, et al.
2-Arachidonoyl-glycerol- and arachidonic acid-stimulated neutrophils release antimicrobial effectors against E. coli, S. aureus, HSV-1, and RSV
.
J Leukoc Biol
.
2013
Feb
;
93
(
2
):
267
76
.
[PubMed]
1938-3673
72.
Massi
P
,
Fuzio
D
,
Viganò
D
,
Sacerdote
P
,
Parolaro
D
.
Relative involvement of cannabinoid CB(1) and CB(2) receptors in the Delta(9)-tetrahydrocannabinol-induced inhibition of natural killer activity
.
Eur J Pharmacol
.
2000
Jan
;
387
(
3
):
343
7
.
[PubMed]
0014-2999
73.
Sugawara
K
,
Biro
T
,
Tsuruta
D
,
Toth
BI
,
Kromminga
A
,
Zakany
N
, et al.
Endocannabinoids limit excessive mast cell maturation and activation in human skin. J Allergy Clin Immunol.
2012
;129(3):726-38 e8.
74.
Ferrini
ME
,
Hong
S
,
Stierle
A
,
Stierle
D
,
Stella
N
,
Roberts
K
, et al.
CB2 receptors regulate natural killer cells that limit allergic airway inflammation in a murine model of asthma
.
Allergy
.
2017
Jun
;
72
(
6
):
937
47
.
[PubMed]
1398-9995
75.
Henriquez
JE
,
Bach
AP
,
Matos-Fernandez
KM
,
Crawford
RB
,
Kaminski
NE
.
Δ9-Tetrahydrocannabinol (THC) Impairs CD8+ T Cell-Mediated Activation of Astrocytes
.
J Neuroimmune Pharmacol
.
2020
Mar
.
[PubMed]
1557-1904
76.
Martín-Fontecha
M
,
Angelina
A
,
Rückert
B
,
Rueda-Zubiaurre
A
,
Martín-Cruz
L
,
van de Veen
W
, et al.
A Fluorescent Probe to Unravel Functional Features of Cannabinoid Receptor CB1 in Human Blood and Tonsil Immune System Cells
.
Bioconjug Chem
.
2018
Feb
;
29
(
2
):
382
9
.
[PubMed]
1520-4812
77.
Dhital
S
,
Stokes
JV
,
Park
N
,
Seo
KS
,
Kaplan
BL
.
Cannabidiol (CBD) induces functional Tregs in response to low-level T cell activation
.
Cell Immunol
.
2017
Feb
;
312
:
25
34
.
[PubMed]
1090-2163
78.
Pereira
JP
,
An
J
,
Xu
Y
,
Huang
Y
,
Cyster
JG
.
Cannabinoid receptor 2 mediates the retention of immature B cells in bone marrow sinusoids
.
Nat Immunol
.
2009
Apr
;
10
(
4
):
403
11
.
[PubMed]
1529-2916
79.
Muppidi
JR
,
Arnon
TI
,
Bronevetsky
Y
,
Veerapen
N
,
Tanaka
M
,
Besra
GS
, et al.
Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone
.
J Exp Med
.
2011
Sep
;
208
(
10
):
1941
8
.
[PubMed]
1540-9538
80.
De Nardo
D
.
Toll-like receptors: Activation, signalling and transcriptional modulation
.
Cytokine
.
2015
Aug
;
74
(
2
):
181
9
.
[PubMed]
1096-0023
81.
Rajan
TS
,
Giacoppo
S
,
Iori
R
,
De Nicola
GR
,
Grassi
G
,
Pollastro
F
, et al.
Anti-inflammatory and antioxidant effects of a combination of cannabidiol and moringin in LPS-stimulated macrophages
.
Fitoterapia
.
2016
Jul
;
112
:
104
15
.
[PubMed]
1873-6971
82.
McCoy
KL
.
Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation
.
Mediators Inflamm
.
2016
;
2016
:
5831315
.
[PubMed]
1466-1861
83.
Fitzpatrick
JK
,
Downer
EJ
.
Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis.
Neuropharmacology.
2017
;113(Pt B):618-26.
84.
van Niekerk
G
,
Mabin
T
,
Engelbrecht
AM
.
Anti-inflammatory mechanisms of cannabinoids: an immunometabolic perspective
.
Inflammopharmacology
.
2019
Feb
;
27
(
1
):
39
46
.
[PubMed]
1568-5608
85.
Kelly
B
,
O’Neill
LA
.
Metabolic reprogramming in macrophages and dendritic cells in innate immunity
.
Cell Res
.
2015
Jul
;
25
(
7
):
771
84
.
[PubMed]
1748-7838
86.
O’Neill
LA
,
Kishton
RJ
,
Rathmell
J
.
A guide to immunometabolism for immunologists
.
Nat Rev Immunol
.
2016
Sep
;
16
(
9
):
553
65
.
[PubMed]
1474-1741
87.
O’Neill
LA
,
Pearce
EJ
.
Immunometabolism governs dendritic cell and macrophage function
.
J Exp Med
.
2016
Jan
;
213
(
1
):
15
23
.
[PubMed]
1540-9538
88.
Mihaylova
MM
,
Shaw
RJ
.
The AMPK signalling pathway coordinates cell growth, autophagy and metabolism
.
Nat Cell Biol
.
2011
Sep
;
13
(
9
):
1016
23
.
[PubMed]
1476-4679
89.
O’Neill
LA
,
Hardie
DG
.
Metabolism of inflammation limited by AMPK and pseudo-starvation
.
Nature
.
2013
Jan
;
493
(
7432
):
346
55
.
[PubMed]
1476-4687
90.
Dando
I
,
Donadelli
M
,
Costanzo
C
,
Dalla Pozza
E
,
D’Alessandro
A
,
Zolla
L
, et al.
Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells
.
Cell Death Dis
.
2013
Jun
;
4
:
e664
.
[PubMed]
2041-4889
91.
Vara
D
,
Salazar
M
,
Olea-Herrero
N
,
Guzmán
M
,
Velasco
G
,
Díaz-Laviada
I
.
Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy
.
Cell Death Differ
.
2011
Jul
;
18
(
7
):
1099
111
.
[PubMed]
1476-5403
92.
Riffelmacher
T
,
Richter
FC
,
Simon
AK
.
Autophagy dictates metabolism and differentiation of inflammatory immune cells
.
Autophagy
.
2018
;
14
(
2
):
199
206
.
[PubMed]
1554-8635
93.
Wei
J
,
Long
L
,
Yang
K
,
Guy
C
,
Shrestha
S
,
Chen
Z
, et al.
Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis
.
Nat Immunol
.
2016
Mar
;
17
(
3
):
277
85
.
[PubMed]
1529-2916
94.
Koay
LC
,
Rigby
RJ
,
Wright
KL
.
Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium
.
Am J Physiol Gastrointest Liver Physiol
.
2014
Jul
;
307
(
2
):
G140
8
.
[PubMed]
1522-1547
95.
Katchan
V
,
David
P
,
Shoenfeld
Y
.
Cannabinoids and autoimmune diseases: A systematic review
.
Autoimmun Rev
.
2016
Jun
;
15
(
6
):
513
28
.
[PubMed]
1873-0183
96.
Simon
HU
,
Yousefi
S
,
Germic
N
,
Arnold
IC
,
Haczku
A
,
Karaulov
AV
, et al.
The Cellular Functions of Eosinophils: Collegium Internationale Allergologicum (CIA) Update 2020
.
Int Arch Allergy Immunol
.
2020
;
181
(
1
):
11
23
.
[PubMed]
1423-0097
97.
Palomares
O
,
Martín-Fontecha
M
,
Lauener
R
,
Traidl-Hoffmann
C
,
Cavkaytar
O
,
Akdis
M
, et al.
Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β
.
Genes Immun
.
2014
Dec
;
15
(
8
):
511
20
.
[PubMed]
1476-5470
98.
Gaffal
E
,
Cron
M
,
Glodde
N
,
Bald
T
,
Kuner
R
,
Zimmer
A
, et al.
Cannabinoid 1 receptors in keratinocytes modulate proinflammatory chemokine secretion and attenuate contact allergic inflammation
.
J Immunol
.
2013
May
;
190
(
10
):
4929
36
.
[PubMed]
1550-6606
99.
Vuolo
F
,
Abreu
SC
,
Michels
M
,
Xisto
DG
,
Blanco
NG
,
Hallak
JE
, et al.
Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma
.
Eur J Pharmacol
.
2019
Jan
;
843
:
251
9
.
[PubMed]
1879-0712
100.
Mimura
T
,
Oka
S
,
Koshimoto
H
,
Ueda
Y
,
Watanabe
Y
,
Sugiura
T
.
Involvement of the endogenous cannabinoid 2 ligand 2-arachidonyl glycerol in allergic inflammation
.
Int Arch Allergy Immunol
.
2012
;
159
(
2
):
149
56
.
[PubMed]
1423-0097
101.
Vandenplas
O
,
Suarthana
E
,
Rifflart
C
,
Lemiere
C
,
Le Moual
N
,
Bousquet
J.
The Impact of Work-Related Rhinitis on Quality of Life and Work Productivity: A General Workforce-Based Survey. J Allergy Clin Immunol Pract.
2020
;8(5):1583-91 e5.
102.
Hellings
PW
,
Fokkens
WJ
,
Bachert
C
,
Akdis
CA
,
Bieber
T
,
Agache
I
, et al.;
ARIA and EPOS working groups
.
Positioning the principles of precision medicine in care pathways for allergic rhinitis and chronic rhinosinusitis - A EUFOREA-ARIA-EPOS-AIRWAYS ICP statement
.
Allergy
.
2017
Sep
;
72
(
9
):
1297
305
.
[PubMed]
1398-9995
103.
Sugawara
K
,
Zákány
N
,
Hundt
T
,
Emelianov
V
,
Tsuruta
D
,
Schäfer
C
, et al.
Cannabinoid receptor 1 controls human mucosal-type mast cell degranulation and maturation in situ
.
J Allergy Clin Immunol
.
2013
Jul
;
132
(
1
):
182
93
.
[PubMed]
1097-6825
104.
Alenmyr
L
,
Högestätt
ED
,
Zygmunt
PM
,
Greiff
L
.
TRPV1-mediated itch in seasonal allergic rhinitis
.
Allergy
.
2009
May
;
64
(
5
):
807
10
.
[PubMed]
1398-9995
105.
Wenzel
SE
.
Asthma phenotypes: the evolution from clinical to molecular approaches
.
Nat Med
.
2012
May
;
18
(
5
):
716
25
.
[PubMed]
1546-170X
106.
Global Initiative for Asthma
.
Global Strategy for Asthma Management and Prevention.
2020
.
107.
Colodenco
D
,
Palomares
O
,
Celis
C
,
Kaplan
A
,
Domingo
C
.
Moving toward consensus on diagnosis and management of severe asthma in adults
.
Curr Med Res Opin
.
2018
Mar
;
34
(
3
):
387
99
.
[PubMed]
1473-4877
108.
Palomares
Ó
,
Sánchez-Ramón
S
,
Dávila
I
,
Prieto
L
,
Pérez de Llano
L
,
Lleonart
M
, et al.
dIvergEnt: How IgE Axis Contributes to the Continuum of Allergic Asthma and Anti-IgE Therapies
.
Int J Mol Sci
.
2017
Jun
;
18
(
6
):
E1328
.
[PubMed]
1422-0067
109.
Agache
I
,
Beltran
J
,
Akdis
C
,
Akdis
M
,
Canelo-Aybar
C
,
Canonica
GW
, et al.
Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma
.
Allergy
.
2020
May
;
75
(
5
):
1023
42
.
[PubMed]
1398-9995
110.
Agache
I
,
Rocha
C
,
Beltran
J
,
Song
Y
,
Posso
M
,
Solà
I
, et al.
Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma: A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma
.
Allergy
.
2020
May
;
75
(
5
):
1043
57
.
[PubMed]
1398-9995
111.
Agache
I
,
Song
Y
,
Rocha
C
,
Beltran
J
,
Posso
M
,
Steiner
C
, et al.
Efficacy and safety of treatment with dupilumab for severe asthma: A systematic review of the EAACI guidelines-Recommendations on the use of biologicals in severe asthma
.
Allergy
.
2020
.0105-4538
112.
Vachon
L
,
FitzGerald
MX
,
Solliday
NH
,
Gould
IA
,
Gaensler
EA
.
Single-dose effects of marihuana smoke. Bronchial dynamics and respiratory-center sensitivity in normal subjects
.
N Engl J Med
.
1973
May
;
288
(
19
):
985
9
.
[PubMed]
0028-4793
113.
Tashkin
DP
,
Reiss
S
,
Shapiro
BJ
,
Calvarese
B
,
Olsen
JL
,
Lodge
JW
.
Bronchial effects of aerosolized delta 9-tetrahydrocannabinol in healthy and asthmatic subjects
.
Am Rev Respir Dis
.
1977
Jan
;
115
(
1
):
57
65
.
[PubMed]
0003-0805
114.
Zoerner
AA
,
Stichtenoth
DO
,
Engeli
S
,
Batkai
S
,
Winkler
C
,
Schaumann
F
, et al.
Allergen challenge increases anandamide in bronchoalveolar fluid of patients with allergic asthma
.
Clin Pharmacol Ther
.
2011
Sep
;
90
(
3
):
388
91
.
[PubMed]
1532-6535
115.
Roviezzo
F
,
Rossi
A
,
Caiazzo
E
,
Orlando
P
,
Riemma
MA
,
Iacono
VM
, et al.
Palmitoylethanolamide Supplementation during Sensitization Prevents Airway Allergic Symptoms in the Mouse
.
Front Pharmacol
.
2017
Dec
;
8
:
857
.
[PubMed]
1663-9812
116.
Stengel
PW
,
Cockerham
SL
,
Silbaugh
SA
.
Inhaled anandamide reduces leukotriene D4-induced airway obstruction in guinea pigs
.
Eur J Pharmacol
.
2007
Feb
;
557
(
1
):
66
8
.
[PubMed]
0014-2999
117.
Calignano
A
,
Kátona
I
,
Désarnaud
F
,
Giuffrida
A
,
La Rana
G
,
Mackie
K
, et al.
Bidirectional control of airway responsiveness by endogenous cannabinoids
.
Nature
.
2000
Nov
;
408
(
6808
):
96
101
.
[PubMed]
0028-0836
118.
Abboud
RT
,
Sanders
HD
.
Effect of oral administration of delta-tetrahydrocannabinol on airway mechanics in normal and asthmatic subjects
.
Chest
.
1976
Oct
;
70
(
4
):
480
5
.
[PubMed]
0012-3692
119.
Bozkurt
TE
,
Kaya
Y
,
Durlu-Kandilci
NT
,
Onder
S
,
Sahin-Erdemli
I
.
The effect of cannabinoids on dinitrofluorobenzene-induced experimental asthma in mice
.
Respir Physiol Neurobiol
.
2016
Sep
;
231
:
7
13
.
[PubMed]
1878-1519
120.
Grassin-Delyle
S
,
Naline
E
,
Buenestado
A
,
Faisy
C
,
Alvarez
JC
,
Salvator
H
, et al.
Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors
.
Br J Pharmacol
.
2014
Jun
;
171
(
11
):
2767
77
.
[PubMed]
1476-5381
121.
Fukuda
H
,
Abe
T
,
Yoshihara
S
.
The cannabinoid receptor agonist WIN 55,212-2 inhibits antigen-induced plasma extravasation in guinea pig airways
.
Int Arch Allergy Immunol
.
2010
;
152
(
3
):
295
300
.
[PubMed]
1423-0097
122.
Yoshihara
S
,
Morimoto
H
,
Ohori
M
,
Yamada
Y
,
Abe
T
,
Arisaka
O
.
Endogenous cannabinoid receptor agonists inhibit neurogenic inflammations in guinea pig airways
.
Int Arch Allergy Immunol
.
2005
Sep
;
138
(
1
):
80
7
.
[PubMed]
1018-2438
123.
Bozkurt
TE
.
Endocannabinoid System in the Airways
.
Molecules
.
2019
Dec
;
24
(
24
):
E4626
.
[PubMed]
1420-3049
124.
Jan
TR
,
Farraj
AK
,
Harkema
JR
,
Kaminski
NE
.
Attenuation of the ovalbumin-induced allergic airway response by cannabinoid treatment in A/J mice
.
Toxicol Appl Pharmacol
.
2003
Apr
;
188
(
1
):
24
35
.
[PubMed]
0041-008X
125.
Giannini
L
,
Nistri
S
,
Mastroianni
R
,
Cinci
L
,
Vannacci
A
,
Mariottini
C
, et al.
Activation of cannabinoid receptors prevents antigen-induced asthma-like reaction in guinea pigs
.
J Cell Mol Med
.
2008
Dec
;
12
6A
:
2381
94
.
[PubMed]
1582-1838
126.
Ribeiro
A
,
Almeida
VI
,
Costola-de-Souza
C
,
Ferraz-de-Paula
V
,
Pinheiro
ML
,
Vitoretti
LB
, et al.
Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury
.
Immunopharmacol Immunotoxicol
.
2015
Feb
;
37
(
1
):
35
41
.
[PubMed]
1532-2513
127.
Abohalaka
R
,
Bozkurt
TE
,
Nemutlu
E
,
Onder
SC
,
Sahin-Erdemli
I
.
The Effects of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Inhibitor treatments on Lipopolysaccharide-induced Airway Inflammation in Mice
.
Pulm Pharmacol Ther
.
2020
May
;
•••
:
101920
.
[PubMed]
1522-9629
128.
Benito-Villalvilla
C
,
Soria
I
,
Pérez-Diego
M
,
Fernández-Caldas
E
,
Subiza
JL
,
Palomares
O
.
Alum impairs tolerogenic properties induced by allergoid-mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs
.
Allergy
.
2020
Mar
;
75
(
3
):
648
59
.
[PubMed]
1398-9995
129.
Benito-Villalvilla
C
,
Soria
I
,
Subiza
JL
,
Palomares
O
.
Novel vaccines targeting dendritic cells by coupling allergoids to mannan
.
Allergo J Int
.
2018
;
27
(
8
):
256
62
.
[PubMed]
2197-0378
130.
Sirvent
S
,
Soria
I
,
Cirauqui
C
,
Cases
B
,
Manzano
AI
,
Diez-Rivero
CM
, et al.
Novel vaccines targeting dendritic cells by coupling allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory T cells through programmed death ligand 1. J Allergy Clin Immunol.
2016
;138(2):558-67 e11.
131.
Palladino
C
,
Narzt
MS
,
Bublin
M
,
Schreiner
M
,
Humeniuk
P
,
Gschwandtner
M
, et al.
Peanut lipids display potential adjuvanticity by triggering a pro-inflammatory response in human keratinocytes
.
Allergy
.
2018
Aug
;
73
(
8
):
1746
9
.
[PubMed]
1398-9995
132.
Palomares
O.
The role of regulatory T cells in IgE-mediated food allergy. J Investig Allergol Clin Immunol.
2013
;23(6):371-82; quiz 2 p preceding 82.
133.
Ali
A
,
Akhtar
N
.
The safety and efficacy of 3% Cannabis seeds extract cream for reduction of human cheek skin sebum and erythema content
.
Pak J Pharm Sci
.
2015
Jul
;
28
(
4
):
1389
95
.
[PubMed]
1011-601X
134.
Karsak
M
,
Gaffal
E
,
Date
R
,
Wang-Eckhardt
L
,
Rehnelt
J
,
Petrosino
S
, et al.
Attenuation of allergic contact dermatitis through the endocannabinoid system
.
Science
.
2007
Jun
;
316
(
5830
):
1494
7
.
[PubMed]
1095-9203
135.
Avila
C
,
Massick
S
,
Kaffenberger
BH
,
Kwatra
SG
,
Bechtel
M
.
Cannabinoids for the treatment of chronic pruritus: A review
.
J Am Acad Dermatol
.
2020
May
;
82
(
5
):
1205
12
.
[PubMed]
1097-6787
136.
López-Abente
J
,
Bernaldo-de-Quirós
E
,
Camino
M
,
Gil
N
,
Panadero
E
,
Campos-Domínguez
M
, et al.
Immune dysregulation and Th2 polarization are associated with atopic dermatitis in heart-transplant children: A delicate balance between risk of rejection or atopic symptoms
.
Am J Transplant
.
2019
May
;
19
(
5
):
1536
44
.
[PubMed]
1600-6143
137.
Simon
D
,
Wollenberg
A
,
Renz
H
,
Simon
HU
.
Atopic Dermatitis: Collegium Internationale Allergologicum (CIA) Update 2019
.
Int Arch Allergy Immunol
.
2019
;
178
(
3
):
207
18
.
[PubMed]
1423-0097
138.
Gaffal
E
,
Glodde
N
,
Jakobs
M
,
Bald
T
,
Tüting
T
.
Cannabinoid 1 receptors in keratinocytes attenuate fluorescein isothiocyanate-induced mouse atopic-like dermatitis
.
Exp Dermatol
.
2014
Jun
;
23
(
6
):
401
6
.
[PubMed]
1600-0625
139.
Roelandt
T
,
Heughebaert
C
,
Bredif
S
,
Giddelo
C
,
Baudouin
C
,
Msika
P
, et al.
Cannabinoid receptors 1 and 2 oppositely regulate epidermal permeability barrier status and differentiation
.
Exp Dermatol
.
2012
Sep
;
21
(
9
):
688
93
.
[PubMed]
1600-0625
140.
Kim
HJ
,
Kim
B
,
Park
BM
,
Jeon
JE
,
Lee
SH
,
Mann
S
, et al.
Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone-induced atopic dermatitis model
.
Int J Dermatol
.
2015
Oct
;
54
(
10
):
e401
8
.
[PubMed]
1365-4632
141.
Nam
G
,
Jeong
SK
,
Park
BM
,
Lee
SH
,
Kim
HJ
,
Hong
SP
, et al.
Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model
.
Ann Dermatol
.
2016
Feb
;
28
(
1
):
22
9
.
[PubMed]
1013-9087
142.
Small-Howard
AL
,
Shimoda
LM
,
Adra
CN
,
Turner
H
.
Anti-inflammatory potential of CB1-mediated cAMP elevation in mast cells
.
Biochem J
.
2005
Jun
;
388
(
Pt 2
):
465
73
.
[PubMed]
1470-8728
143.
Petrosino
S
,
Cristino
L
,
Karsak
M
,
Gaffal
E
,
Ueda
N
,
Tüting
T
, et al.
Protective role of palmitoylethanolamide in contact allergic dermatitis
.
Allergy
.
2010
Jun
;
65
(
6
):
698
711
.
[PubMed]
1398-9995
144.
Ständer
S
,
Reinhardt
HW
,
Luger
TA
.
[Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus]
.
Hautarzt
.
2006
Sep
;
57
(
9
):
801
7
.
[PubMed]
0017-8470
145.
Oláh
A
,
Ambrus
L
,
Nicolussi
S
,
Gertsch
J
,
Tubak
V
,
Kemény
L
, et al.
Inhibition of fatty acid amide hydrolase exerts cutaneous anti-inflammatory effects both in vitro and in vivo
.
Exp Dermatol
.
2016
Apr
;
25
(
4
):
328
30
.
[PubMed]
1600-0625
146.
Sasso
O
,
Summa
M
,
Armirotti
A
,
Pontis
S
,
De Mei
C
,
Piomelli
D
.
The N-Acylethanolamine Acid Amidase Inhibitor ARN077 Suppresses Inflammation and Pruritus in a Mouse Model of Allergic Dermatitis
.
J Invest Dermatol
.
2018
Mar
;
138
(
3
):
562
9
.
[PubMed]
1523-1747
147.
Kozela
E
,
Juknat
A
,
Kaushansky
N
,
Ben-Nun
A
,
Coppola
G
,
Vogel
Z
.
Cannabidiol, a non-psychoactive cannabinoid, leads to EGR2-dependent anergy in activated encephalitogenic T cells
.
J Neuroinflammation
.
2015
Mar
;
12
:
52
.
[PubMed]
1742-2094
148.
Harvey
BS
,
Sia
TC
,
Wattchow
DA
,
Smid
SD
.
Interleukin 17A evoked mucosal damage is attenuated by cannabidiol and anandamide in a human colonic explant model
.
Cytokine
.
2014
Feb
;
65
(
2
):
236
44
.
[PubMed]
1096-0023
149.
De Filippis
D
,
Esposito
G
,
Cirillo
C
,
Cipriano
M
,
De Winter
BY
,
Scuderi
C
, et al.
Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis
.
PLoS One
.
2011
;
6
(
12
):
e28159
.
[PubMed]
1932-6203
150.
Lee
WS
,
Erdelyi
K
,
Matyas
C
,
Mukhopadhyay
P
,
Varga
ZV
,
Liaudet
L
, et al.
Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation
.
Mol Med
.
2016
Sep
;
22
:
136
46
.
[PubMed]
1528-3658
151.
Tawada
C
,
Kanoh
H
,
Nakamura
M
,
Mizutani
Y
,
Fujisawa
T
,
Banno
Y
, et al.
Interferon-γ decreases ceramides with long-chain fatty acids: possible involvement in atopic dermatitis and psoriasis
.
J Invest Dermatol
.
2014
Mar
;
134
(
3
):
712
8
.
[PubMed]
1523-1747
152.
Palmieri
B
,
Laurino
C
,
Vadalà
M
.
A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars
.
Clin Ter
.
2019
Mar-Apr
;
170
(
2
):
e93
9
.
[PubMed]
1972-6007
153.
Haruna
T
,
Soga
M
,
Morioka
Y
,
Imura
K
,
Furue
Y
,
Yamamoto
M
, et al.
The Inhibitory Effect of S-777469, a Cannabinoid Type 2 Receptor Agonist, on Skin Inflammation in Mice
.
Pharmacology
.
2017
;
99
(
5-6
):
259
67
.
[PubMed]
1423-0313
154.
Kaplan
DH
,
Igyártó
BZ
,
Gaspari
AA
.
Early immune events in the induction of allergic contact dermatitis
.
Nat Rev Immunol
.
2012
Jan
;
12
(
2
):
114
24
.
[PubMed]
1474-1741
155.
Schmidt
M
,
Raghavan
B
,
Müller
V
,
Vogl
T
,
Fejer
G
,
Tchaptchet
S
, et al.
Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel
.
Nat Immunol
.
2010
Sep
;
11
(
9
):
814
9
.
[PubMed]
1529-2916
156.
Watanabe
H
,
Gaide
O
,
Pétrilli
V
,
Martinon
F
,
Contassot
E
,
Roques
S
, et al.
Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity
.
J Invest Dermatol
.
2007
Aug
;
127
(
8
):
1956
63
.
[PubMed]
1523-1747
157.
Engeman
T
,
Gorbachev
AV
,
Kish
DD
,
Fairchild
RL
.
The intensity of neutrophil infiltration controls the number of antigen-primed CD8 T cells recruited into cutaneous antigen challenge sites
.
J Leukoc Biol
.
2004
Nov
;
76
(
5
):
941
9
.
[PubMed]
0741-5400
158.
Kish
DD
,
Gorbachev
AV
,
Parameswaran
N
,
Gupta
N
,
Fairchild
RL
.
Neutrophil expression of Fas ligand and perforin directs effector CD8 T cell infiltration into antigen-challenged skin
.
J Immunol
.
2012
Sep
;
189
(
5
):
2191
202
.
[PubMed]
1550-6606
159.
Kish
DD
,
Li
X
,
Fairchild
RL
.
CD8 T cells producing IL-17 and IFN-gamma initiate the innate immune response required for responses to antigen skin challenge
.
J Immunol
.
2009
May
;
182
(
10
):
5949
59
.
[PubMed]
1550-6606
160.
Petrosino
S
,
Verde
R
,
Vaia
M
,
Allarà
M
,
Iuvone
T
,
Di Marzo
V
.
Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis
.
J Pharmacol Exp Ther
.
2018
Jun
;
365
(
3
):
652
63
.
[PubMed]
1521-0103
161.
Vaia
M
,
Petrosino
S
,
De Filippis
D
,
Negro
L
,
Guarino
A
,
Carnuccio
R
, et al.
Palmitoylethanolamide reduces inflammation and itch in a mouse model of contact allergic dermatitis
.
Eur J Pharmacol
.
2016
Nov
;
791
:
669
74
.
[PubMed]
1879-0712
162.
Sampson
HA
,
O’Mahony
L
,
Burks
AW
,
Plaut
M
,
Lack
G
,
Akdis
CA
.
Mechanisms of food allergy
.
J Allergy Clin Immunol
.
2018
Jan
;
141
(
1
):
11
9
.
[PubMed]
1097-6825
163.
Burks
AW
,
Sampson
HA
,
Plaut
M
,
Lack
G
,
Akdis
CA
.
Treatment for food allergy
.
J Allergy Clin Immunol
.
2018
Jan
;
141
(
1
):
1
9
.
[PubMed]
1097-6825
164.
Yu
W
,
Freeland
DM
,
Nadeau
KC
.
Food allergy: immune mechanisms, diagnosis and immunotherapy
.
Nat Rev Immunol
.
2016
Dec
;
16
(
12
):
751
65
.
[PubMed]
1474-1741
165.
Moreira
FA
,
Grieb
M
,
Lutz
B
.
Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression
.
Best Pract Res Clin Endocrinol Metab
.
2009
Feb
;
23
(
1
):
133
44
.
[PubMed]
1878-1594
166.
Morales
P
,
Hernandez-Folgado
L
,
Goya
P
,
Jagerovic
N
. Cannabinoid receptor 2 (CB2) agonists and antagonists: a patent update. Expert Opin Ther Pat.
2016
;26(7):843-56.
167.
Marchalant
Y
,
Brownjohn
PW
,
Bonnet
A
,
Kleffmann
T
,
Ashton
JC
.
Validating Antibodies to the Cannabinoid CB2 Receptor: Antibody Sensitivity Is Not Evidence of Antibody Specificity
.
J Histochem Cytochem
.
2014
Jun
;
62
(
6
):
395
404
.
[PubMed]
1551-5044
168.
Grimsey
NL
,
Goodfellow
CE
,
Scotter
EL
,
Dowie
MJ
,
Glass
M
,
Graham
ES
.
Specific detection of CB1 receptors; cannabinoid CB1 receptor antibodies are not all created equal!
J Neurosci Methods
.
2008
Jun
;
171
(
1
):
78
86
.
[PubMed]
0165-0270
169.
Yates
AS
,
Doughty
SW
,
Kendall
DA
,
Kellam
B
.
Chemical modification of the naphthoyl 3-position of JWH-015: in search of a fluorescent probe to the cannabinoid CB2 receptor
.
Bioorg Med Chem Lett
.
2005
Aug
;
15
(
16
):
3758
62
.
[PubMed]
0960-894X
170.
Martín-Couce
L
,
Martín-Fontecha
M
,
Palomares
O
,
Mestre
L
,
Cordomí
A
,
Hernangomez
M
, et al.
Chemical probes for the recognition of cannabinoid receptors in native systems
.
Angew Chem Int Ed Engl
.
2012
Jul
;
51
(
28
):
6896
9
.
[PubMed]
1521-3773
171.
Petrov
RR
,
Ferrini
ME
,
Jaffar
Z
,
Thompson
CM
,
Roberts
K
,
Diaz
P
.
Design and evaluation of a novel fluorescent CB2 ligand as probe for receptor visualization in immune cells
.
Bioorg Med Chem Lett
.
2011
Oct
;
21
(
19
):
5859
62
.
[PubMed]
1464-3405
172.
Westphal
MV
,
Sarott
RC
,
Zirwes
EA
,
Osterwald
A
,
Guba
W
,
Ullmer
C
, et al.
Highly Selective, Amine-Derived Cannabinoid Receptor 2 Probes
.
Chemistry
.
2020
Jan
;
26
(
6
):
1380
7
.
[PubMed]
1521-3765
173.
Soethoudt
M
,
Alachouzos
G
,
van Rooden
EJ
,
Moya-Garzón
MD
,
van den Berg
RJ
,
Heitman
LH
, et al.
Development of a Cannabinoid-Based Photoaffinity Probe to Determine the Δ8/9-Tetrahydrocannabinol Protein Interaction Landscape in Neuroblastoma Cells
.
Cannabis Cannabinoid Res
.
2018
Jul
;
3
(
1
):
136
51
.
[PubMed]
2378-8763
174.
Singh
S
,
Oyagawa
CR
,
Macdonald
C
,
Grimsey
NL
,
Glass
M
,
Vernall
AJ
.
Chromenopyrazole-based High Affinity, Selective Fluorescent Ligands for Cannabinoid Type 2 Receptor
.
ACS Med Chem Lett
.
2019
Jan
;
10
(
2
):
209
14
.
[PubMed]
1948-5875
175.
Wu
Z
,
Shao
P
,
Zhang
S
,
Ling
X
,
Bai
M
.
Molecular imaging of human tumor cells that naturally overexpress type 2 cannabinoid receptors using a quinolone-based near-infrared fluorescent probe
.
J Biomed Opt
.
2014
;
19
(
7
):
76016
.
[PubMed]
1560-2281
176.
Kulkarni
PM
,
Kulkarni
AR
,
Korde
A
,
Tichkule
RB
,
Laprairie
RB
,
Denovan-Wright
EM
, et al.
Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)
.
J Med Chem
.
2016
Jan
;
59
(
1
):
44
60
.
[PubMed]
1520-4804
177.
Blankman
JL
,
Cravatt
BF
.
Chemical probes of endocannabinoid metabolism
.
Pharmacol Rev
.
2013
Mar
;
65
(
2
):
849
71
.
[PubMed]
1521-0081
178.
Chicca
A
,
Nicolussi
S
,
Bartholomäus
R
,
Blunder
M
,
Aparisi Rey
A
,
Petrucci
V
, et al.
Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake
.
Proc Natl Acad Sci U S A
.
2017
Jun
;
114
(
25
):
E5006
15
.
[PubMed]
1091-6490
179.
Turcotte
C
,
Dumais
É
,
Archambault
AS
,
Martin
C
,
Blanchet
MR
,
Bissonnette
É
, et al.
Human leukocytes differentially express endocannabinoid-glycerol lipases and hydrolyze 2-arachidonoyl-glycerol and its metabolites from the 15-lipoxygenase and cyclooxygenase pathways
.
J Leukoc Biol
.
2019
Dec
;
106
(
6
):
1337
47
.
[PubMed]
1938-3673
180.
Hsu
KL
,
Tsuboi
K
,
Adibekian
A
,
Pugh
H
,
Masuda
K
,
Cravatt
BF
.
DAGLβ inhibition perturbs a lipid network involved in macrophage inflammatory responses
.
Nat Chem Biol
.
2012
Dec
;
8
(
12
):
999
1007
.
[PubMed]
1552-4469
181.
Shin
M
,
Buckner
A
,
Prince
J
,
Bullock
TNJ
,
Hsu
KL
. Diacylglycerol Lipase-beta Is Required for TNF-alpha Response but Not CD8(+) T Cell Priming Capacity of Dendritic Cells. Cell Chem Biol.
2019
;26(7):1036-41 e3.
182.
Pacher
P
,
Kunos
G
.
Modulating the endocannabinoid system in human health and disease—successes and failures
.
FEBS J
.
2013
May
;
280
(
9
):
1918
43
.
[PubMed]
1742-4658
183.
A Phase Ib/IIa, Double-Blind, Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of S-777469 in Subjects With Atopic Dermatitis [Available from: https://ClinicalTrials.gov/show/NCT00697710
184.
Chiurchiù
V
,
Lanuti
M
,
Catanzaro
G
,
Fezza
F
,
Rapino
C
,
Maccarrone
M
.
Detailed characterization of the endocannabinoid system in human macrophages and foam cells, and anti-inflammatory role of type-2 cannabinoid receptor
.
Atherosclerosis
.
2014
Mar
;
233
(
1
):
55
63
.
[PubMed]
1879-1484
185.
Staiano
RI
,
Loffredo
S
,
Borriello
F
,
Iannotti
FA
,
Piscitelli
F
,
Orlando
P
, et al.
Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors
.
J Leukoc Biol
.
2016
Apr
;
99
(
4
):
531
40
.
[PubMed]
1938-3673
186.
Gallily
R
,
Breuer
A
,
Mechoulam
R
.
2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-alpha production in murine macrophages, and in mice
.
Eur J Pharmacol
.
2000
Oct
;
406
(
1
):
R5
7
.
[PubMed]
0014-2999
187.
Chang
YH
,
Lee
ST
,
Lin
WW
.
Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids
.
J Cell Biochem
.
2001
;
81
(
4
):
715
23
.
[PubMed]
0730-2312
188.
Shiratsuchi
A
,
Watanabe
I
,
Yoshida
H
,
Nakanishi
Y
.
Involvement of cannabinoid receptor CB2 in dectin-1-mediated macrophage phagocytosis
.
Immunol Cell Biol
.
2008
Feb
;
86
(
2
):
179
84
.
[PubMed]
0818-9641
189.
Redlich
S
,
Ribes
S
,
Schütze
S
,
Nau
R
.
Palmitoylethanolamide stimulates phagocytosis of Escherichia coli K1 by macrophages and increases the resistance of mice against infections
.
J Neuroinflammation
.
2014
Jun
;
11
:
108
.
[PubMed]
1742-2094
190.
Hao
MX
,
Jiang
LS
,
Fang
NY
,
Pu
J
,
Hu
LH
,
Shen
LH
, et al.
The cannabinoid WIN55,212-2 protects against oxidized LDL-induced inflammatory response in murine macrophages
.
J Lipid Res
.
2010
Aug
;
51
(
8
):
2181
90
.
[PubMed]
1539-7262
191.
Wu
HY
,
Huang
CH
,
Lin
YH
,
Wang
CC
,
Jan
TR
.
Cannabidiol induced apoptosis in human monocytes through mitochondrial permeability transition pore-mediated ROS production
.
Free Radic Biol Med
.
2018
Aug
;
124
:
311
8
.
[PubMed]
1873-4596
192.
Roth
MD
,
Castaneda
JT
,
Kiertscher
SM
.
Exposure to Δ9-Tetrahydrocannabinol Impairs the Differentiation of Human Monocyte-derived Dendritic Cells and their Capacity for T cell Activation
.
J Neuroimmune Pharmacol
.
2015
Jun
;
10
(
2
):
333
43
.
[PubMed]
1557-1904
193.
Graham
ES
,
Angel
CE
,
Schwarcz
LE
,
Dunbar
PR
,
Glass
M
.
Detailed characterisation of CB2 receptor protein expression in peripheral blood immune cells from healthy human volunteers using flow cytometry
.
Int J Immunopathol Pharmacol
.
2010
Jan-Mar
;
23
(
1
):
25
34
.
[PubMed]
0394-6320
194.
McHugh
D
,
Tanner
C
,
Mechoulam
R
,
Pertwee
RG
,
Ross
RA
.
Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2
.
Mol Pharmacol
.
2008
Feb
;
73
(
2
):
441
50
.
[PubMed]
1521-0111
195.
Oka
S
,
Ikeda
S
,
Kishimoto
S
,
Gokoh
M
,
Yanagimoto
S
,
Waku
K
, et al.
2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces the migration of EoL-1 human eosinophilic leukemia cells and human peripheral blood eosinophils
.
J Leukoc Biol
.
2004
Nov
;
76
(
5
):
1002
9
.
[PubMed]
0741-5400
196.
Kishimoto
S
,
Oka
S
,
Gokoh
M
,
Sugiura
T
.
Chemotaxis of human peripheral blood eosinophils to 2-arachidonoylglycerol: comparison with other eosinophil chemoattractants
.
Int Arch Allergy Immunol
.
2006
;
140
Suppl 1
:
3
7
.
[PubMed]
1018-2438
197.
Hernández-Cervantes
R
,
Pérez-Torres
A
,
Prospéro-García
Ó
,
Morales Montor
J
.
Gestational exposure to the cannabinoid WIN 55,212-2 and its effect on the innate intestinal immune response
.
Sci Rep
.
2019
Dec
;
9
(
1
):
20340
.
[PubMed]
2045-2322
198.
Facci
L
,
Dal Toso
R
,
Romanello
S
,
Buriani
A
,
Skaper
SD
,
Leon
A
.
Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide
.
Proc Natl Acad Sci U S A
.
1995
Apr
;
92
(
8
):
3376
80
.
[PubMed]
0027-8424
199.
Cruz
SL
,
Sánchez-Miranda
E
,
Castillo-Arellano
JI
,
Cervantes-Villagrana
RD
,
Ibarra-Sánchez
A
,
González-Espinosa
C
.
Anandamide inhibits FcεRI-dependent degranulation and cytokine synthesis in mast cells through CB2 and GPR55 receptor activation. Possible involvement of CB2-GPR55 heteromers
.
Int Immunopharmacol
.
2018
Nov
;
64
:
298
307
.
[PubMed]
1878-1705
200.
Baban
B
,
Khodadadi
H
,
Vaibhav
K
,
Marchetti
C
,
Riccardi
C
,
Mozaffari
MS
.
Regulation of Innate Lymphoid Cells in Acute Kidney Injury: crosstalk between Cannabidiol and GILZ
.
J Immunol Res
.
2020
Feb
;
2020
:
6056373
.
[PubMed]
2314-7156
201.
Cencioni
MT
,
Chiurchiù
V
,
Catanzaro
G
,
Borsellino
G
,
Bernardi
G
,
Battistini
L
, et al.
Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors
.
PLoS One
.
2010
Jan
;
5
(
1
):
e8688
.
[PubMed]
1932-6203
202.
Robinson
RH
,
Meissler
JJ
,
Breslow-Deckman
JM
,
Gaughan
J
,
Adler
MW
,
Eisenstein
TK
.
Cannabinoids inhibit T-cells via cannabinoid receptor 2 in an in vitro assay for graft rejection, the mixed lymphocyte reaction
.
J Neuroimmune Pharmacol
.
2013
Dec
;
8
(
5
):
1239
50
.
[PubMed]
1557-1904
203.
Maresz
K
,
Pryce
G
,
Ponomarev
ED
,
Marsicano
G
,
Croxford
JL
,
Shriver
LP
, et al.
Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells
.
Nat Med
.
2007
Apr
;
13
(
4
):
492
7
.
[PubMed]
1078-8956
204.
Gentili
M
,
Ronchetti
S
,
Ricci
E
,
Di Paola
R
,
Gugliandolo
E
,
Cuzzocrea
S
, et al.
Selective CB2 inverse agonist JTE907 drives T cell differentiation towards a Treg cell phenotype and ameliorates inflammation in a mouse model of inflammatory bowel disease
.
Pharmacol Res
.
2019
Mar
;
141
:
21
31
.
[PubMed]
1096-1186
205.
Galiègue
S
,
Mary
S
,
Marchand
J
,
Dussossoy
D
,
Carrière
D
,
Carayon
P
, et al.
Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations
.
Eur J Biochem
.
1995
Aug
;
232
(
1
):
54
61
.
[PubMed]
0014-2956
206.
Derocq
JM
,
Ségui
M
,
Marchand
J
,
Le Fur
G
,
Casellas
P
.
Cannabinoids enhance human B-cell growth at low nanomolar concentrations
.
FEBS Lett
.
1995
Aug
;
369
(
2-3
):
177
82
.
[PubMed]
0014-5793
207.
Agudelo
M
,
Newton
C
,
Widen
R
,
Sherwood
T
,
Nong
L
,
Friedman
H
, et al.
Cannabinoid receptor 2 (CB2) mediates immunoglobulin class switching from IgM to IgE in cultures of murine-purified B lymphocytes
.
J Neuroimmune Pharmacol
.
2008
Mar
;
3
(
1
):
35
42
.
[PubMed]
1557-1904
208.
Soethoudt
M
,
Stolze
SC
,
Westphal
MV
,
van Stralen
L
,
Martella
A
,
van Rooden
EJ
, et al.
Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells
.
J Am Chem Soc
.
2018
May
;
140
(
19
):
6067
75
.
[PubMed]
1520-5126
209.
Hsu
KL
,
Tsuboi
K
,
Whitby
LR
,
Speers
AE
,
Pugh
H
,
Inloes
J
, et al.
Development and optimization of piperidyl-1,2,3-triazole ureas as selective chemical probes of endocannabinoid biosynthesis
.
J Med Chem
.
2013
Nov
;
56
(
21
):
8257
69
.
[PubMed]
1520-4804
210.
Baggelaar
MP
,
Janssen
FJ
,
van Esbroeck
AC
,
den Dulk
H
,
Allarà
M
,
Hoogendoorn
S
, et al.
Development of an activity-based probe and in silico design reveal highly selective inhibitors for diacylglycerol lipase-α in brain
.
Angew Chem Int Ed Engl
.
2013
Nov
;
52
(
46
):
12081
5
.
[PubMed]
1521-3773
211.
Miceli
M
,
Casati
S
,
Ottria
R
,
Di Leo
S
,
Eberini
I
,
Palazzolo
L
, et al.
Set-Up and Validation of a High Throughput Screening Method for Human Monoacylglycerol Lipase (MAGL) Based on a New Red Fluorescent Probe
.
Molecules
.
2019
Jun
;
24
(
12
):
E2241
.
[PubMed]
1420-3049
212.
Liu
Y
,
Patricelli
MP
,
Cravatt
BF
.
Activity-based protein profiling: the serine hydrolases
.
Proc Natl Acad Sci U S A
.
1999
Dec
;
96
(
26
):
14694
9
.
[PubMed]
0027-8424
213.
Janssen
AP
,
van der Vliet
D
,
Bakker
AT
,
Jiang
M
,
Grimm
SH
,
Campiani
G
, et al.
Development of a Multiplexed Activity-Based Protein Profiling Assay to Evaluate Activity of Endocannabinoid Hydrolase Inhibitors
.
ACS Chem Biol
.
2018
Sep
;
13
(
9
):
2406
13
.
[PubMed]
1554-8937
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.