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Early phytocannabinoid chemistry to endocannabinoids and beyond

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Early phytocannabinoid chemistry to endocannabinoids and beyond

Abstract and Figures

Isolation and structure elucidation of most of the major cannabinoid constituents - including Δ(9)-tetrahydrocannabinol (Δ(9)-THC), which is the principal psychoactive molecule in Cannabis sativa - was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.
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The plant Cannabis sativa and its many
preparations (for example, marijuana,
hashis h, bhang and ganja) have been used
for millennia for recreation (and at times for
the achievement of religious ecstasy) as well
as in medicine. In ancient China, cannabis
was prescribed (together with other plants,
as is customary in Chinese medicine) for
numerous diseases, but it was noted that
when taken in excess it could lead to ‘see-
ing devils’. In Assyria (about 800 ), it was
named both gan-zi-gun-nu (‘the drug that
takes away the mind’) and azallu (when
used as a therapeutic). In India, ancient
Persia and medieval Arab societies, can-
nabis use proceeded along these two diver-
gent routes1. In many countries, hemp — a
strain of Cannabis sativa that does not cause
psychoactivity — was grown for its durable
fibres. Our present-day society follows a
long tradition of recreational, industrial and
medical cannabis use.
Cannabinoid discovery — early history
The behavioural effects of cannabis, in sev-
eral animal species as well as in humans,
were observed in the mid-nineteenth
century2 (FIG.1). These experimental obser-
vations led to the first attempts to isolate
the active constituents of the plant, as had
already been done with other plants that
had known neuropharmacological activ-
ity — for example, the isolation of mor-
phine. A prize was even awarded in 1855
for the ‘successful’ accomplishment of this
project. However, the first isolation of a
plant cannabinoid — named cannabinol
(CBN) — was not achieved until the end
of the nineteenth century. Its structure was
elucidated much later, in the 1930s, by the
groups of Cahn and Todd in the United
Kingdom and by Adams in the United
States, when a further component, can-
nabidiol (CBD), was isolated; however, its
structure could not be elucidated at that
time. Although considerable effort was
invested on the isolation and the elucida-
tion of the structure of the main psycho-
active constituents of cannabis, this goal
was not reached at that time. A synthetic
compound, 6a,10a-tetrahydrocannabinol
(6a,10a-THC), showed pharmacological
activity that paralleled the activity of canna-
bis extracts. Therefore, it was assumed that
6a,10a-THC was chemically related to the
active compounds of the plant (FIG.2). Much
of the early research in this area was done
using synthetic 6a,10a-THC, which is now
known to be considerably less potent than
the actual natural product. The chemical
and pharmacological work that was carried
out until the mid 1940s has been reviewed
elsewhere3–5. Some 6a,10a-THC analogues
were even tested in humans. In light of
recent media reports about the action
of cannabinoids in paediatric epilepsy, it
is of interest to note that a derivative of syn-
thetic 6a,10a-THC (at doses of 1.2–1.8 mg
daily) was administered to a small num-
ber of children with epilepsy and showed
positive results. Historical cannabis use in
medicine over the ages and early chemical
investigations are reviewed in REF.1.
The reasons for the lack of progress
were mostly technical. We now know that
cannabinoids are present in cannabis as a
mixture of many closely related constitu-
ents — over 100 — which were difficult to
separate using the methods that were avail-
able in the nineteenth and early twentieth
centuries. As the active constituents of can-
nabis were not available in pure form, there
was very little biological or clinical work
done in this area from the late 1940s until
the mid 1960s.
By the 1960s, chromatography meth-
ods were well developed for the isolation
of pure compounds from mixtures and
the availability of novel spectrometric
methods meant that the elucidation of the
structure of these compounds was possible.
Indeed, many cannabinoids were isolated,
including 9-THC, which was reported
by Gaoni and Mechoulam in 1964 (REF.6)
(FIG.2). Their structures were mainly elu-
cidated using NMR, which was a modern
method at the time. Several total syntheses
of these compounds have been reported
and most cannabinoids are now available
as both natural and synthetic products.
The chemical work until the mid 1970s is
reviewed in REF.7.
The next step in cannabinoid research was
the elucidation of the metabolism of 9-THC
and later of CBD. The major metabolic path-
way of 9-THC is hydroxylation, which leads
to the formation of an active metabolite, fol-
lowed by its further oxidation to an inactive
acid, which then binds to a sugar molecule.
These acid-derived metabolites are stored in
fatty tissues and are slowly released8. Indeed,
the major final 9-THC metabolite (a car-
boxylic acid that is present as a glucuronide)
can be detected in human urine for several
weeks after cannabis use (FIG.2).
THE ENDOCANNABINOID SYSTEM — TIMELINE
Early phytocannabinoid chemistry
to endocannabinoids and beyond
Raphael Mechoulam, Lumír O. Hanuš, Roger Pertwee and
Allyn C. Howlett
Abstract | Isolation and structure elucidation of most of the major cannabinoid
constituents — including 9-tetrahydrocannabinol (9-THC), which is the principal
psychoactive molecule in Cannabis sativa — was achieved in the 1960s and 1970s.
It was followed by the identification of two cannabinoid receptors in the 1980s and
the early 1990s and by the identification of the endocannabinoids shortly
thereafter.There have since been considerable advances in our understanding of
the endocannabinoid system and its function in the brain, which reveal potential
therapeutic targets for a wide range of brain disorders.
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Early neuropharmacology
The advances in the chemistry of plant and
synthetic cannabinoids led to renewed inter-
est in their neuropharmacology. Loewe5 had
found that cannabis extracts (presumably
containing high levels of what is now known
to be 9-THC and additional phytocan-
nabinoids) can induce catalepsy in mice and
that CBN can also produce this effect, albeit
much less potently than the impure THC
isolated from the resin. It was these findings
that prompted the development by Pertwee9
in 1972 of a quantitative invivo assay for
psychotropic cannabinoids, known as the
ring test, in which the proportion of time
that a mouse placed across an elevated hori-
zontal ring remains immobile or cataleptic is
measured over a 5 minute period9. Martin10
later used this assay, along with three other
bioassays, in what came to be known as the
‘mouse tetrad assay’10. These other assays
provide measures of cannabinoid-induced
hypokinesi a, hypothermia and antinociception
in mice, using a tail flick or hot plate test.
The mouse tetrad assay is a useful invivo
screen for psychotropic cannabinoids, all
of which, in contrast to many other types
of drugs, generally show similar potency in
all four of these bioassays. It was also dis-
covered in the 1940s that cannabinoids can
elicit central excitant activity in rabbits and
mice and corneal arreflexia in rabbits, and
that some phytocannabinoids, particularly
CBD, can prolong barbiturate-induced sleep
by a mechanism that was subsequently dis-
covered to involve the inhibition of certain
cytochrom e P450 (CYP) enzymes10.
Following its identification as the main
psychoactive constituent of cannabis,
9-THC attracted particular attention10,11; for
example, results obtained from several inves-
tigations on humans indicated that when
9-THC was taken orally or intravenously
or when it was inhaled in smoke, it showed
substantial potency at producing psycho-
logical changes similar to those reportedly
experienced in response to recreationally
consumed cannabis11. A few other phyto-
cannabinoids, such as CBN, were found to
induce cannabis-like effects in humans with
low potency (an exception being 8-THC
but there is usually very little 8-THC in
cannabis)11.
It is noteworthy that one synthetic
analogue of 9-THC, nabilone (Cesamet;
Valeant Pharmaceuticals North America)
was approved in 1981 as a medicine for the
suppression of the nausea and vomiting
that is produced by chemotherapy12. Syn-
thetic 9-THC, dronabinol (Marinol; Solvay
Pharmaceuticals, Inc) subsequently entered
Isolation of first plant
cannabinoid, cannabinol104
Cannabidiol
isolation3,4
Early pharmacological
investigations5
Δ9-THC isolation and
structure elucidation6
Isolation and structure
elucidation of 2-AG32,107
Research on cannabinoid
pharmacology and metabolism8,9,15
Discovery of CB1 (REF. 27)
Isolation and structure
elucidation of anandamide30
Discovery of SR-141716A,
the first CB1 antagonist50
Cloning of the first
endocannabinoid-degrading
enzyme, FAAH108
Discovery of retrograde
signalling by
endocannabinoids45
Anandamide
activates vanilloid
receptors109,110
O’Shaughnessy
investigates medicinal
use of cannabis in India2
Synthesis and evaluation
of Δ6a,10a-THC3–5
Cannabidiol structure
elucidation106
Isolation and identification
of additional cannabinoids7
Ring immobility and
tetrad assays9,10
Cloning of CB1
(REF. 29)
Discovery of
CB2 (REF. 31)
Discovery of SR-144528, the first
CB2 antagonist66
Cannabinol structure
elucidation3,4,105
Cloning of the first endocannabinoid-
biosynthesizing enzyme119
Discovery and evaluation of
endocannabinoid-like brain
components95,96,111, discovery and
evaulation of functions of FAAH and MAGL
inhibitors33,83,112,113, cell biology114 and
neuroscience studies carried out115,116 and
clinical trials initiated101,117,118
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1838
1843
1899
1932
1940
1941
1942
1950
1963
1964
1975
1970
1972
1988
1990
1992
1993
1994
1995
1996
1998
1999
2000
2001
2003
2014
Figure 1 | Cannabinoid and endocannabinoid research — a timeline. Almost all early research
was devoted to clarification of cannabinoid chemistry3,4,104,105, and pharmacology was mainly done
using synthetic com pounds5. Following the isolation and structure elucidation of the plant can-
nabinoids, particularly of cannabidiol106 and of Δ9-tetrahydrocannabinol (Δ9-THC)6, pharmaco-
logical and physiological work was initiated8,9,15. The identification of cannabinoid receptors24,29,31,
of endogenous cannabinoids30,32,107 and of receptor antagonists50,66 made possible extensive phar-
macological and neurobiological research leading to cloning of the anandamide-degrading
enzyme fatty acid amide hydrolase (FAAH)108, the discovery of retrograde signaling by
2-arachidonoy l glycerol (2-AG)45, the discovery of allosteric sites on cannabi noid receptor 1
(CB1)33, the discovery that endocannabinoids bind to receptors other than CB1 and CB2
(REFS109–111), the discovery and evaluation of endocannabinoid-like molecules in the brain95,96
and the discovery and function of inhibitors of the endocannabinoid-degrading enzymes112,113.
Cell biology114 and neuroscience115,116 investigations were also carried out, and clinical trials were
initiated101,117,118. Cloning of DAG lipase was also reported119.
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the clinic as a licensed medicine, in 1985
as an antiemetic and in 1992 as an appetite
stimulant12. Claims from patients that can-
nabis can ameliorate unwanted symptoms
of multiple sclerosis also encouraged the
development of the cannabis-based medi-
cine naviximols12 (Sativex; GWPharma),
which contains both 9-THC and the non-
psychoactive CBD; this was first licensed as
a medicine in 2005 in Canada for the relief
of pain experienced by adult patients suf-
fering from multiple sclerosis or advanced
cancer, and subsequently as a medicine to
ameliorate spasticity caused by multiple
sclerosis12.
Discovery of the cannabinoid receptors
Although a considerable amount of phar-
macological work was done on the activity
of 9-THC, its mechanism of action was
not elucidated for more than 20years after
its identification. Indeed, it was originally
thought that the mode of action of 9-THC
was nonspecific in nature and that it might
involve interactions with lipid membranes.
However, although the stereospecificity of
the action of 9-THC and related synthetic
cannabinoids13,14, as well as pharmacological
studies, in humans and animals had sug-
gested a putative cannabinoid receptor15,16,
it was not until the 1980s that evidence for a
protein receptor was sought.
As the family of known G proteins
expanded in the late 1970s and early 1980s,
so did the list of receptors for hormones
and neurotransmitters to which they could
couple. Agonists of opioid, muscarinic, cho-
linergic and α-adrenergic receptors resulted
in inhibition of Gs-stimulated adenylyl
cyclase17–19, and functional homology with
these neuromodulators led to the discov-
ery that cannabinoids also inhibited this
enzyme20–22 by a pertussis toxin-sensitive
mechanism23. This clearly indicated that the
cannabinoid receptor was a G protein-coupled
receptor (GPCR).
From the structure–activity relationship
(SAR) established using cannabimimetic
compounds from Pfizer Central Research, the
Howlett laboratory identified CP55940 (FIG.2)
as a highly potent cannabinoid analogue
and, in 1988, reported the determination and
characterization of a cannabinoid receptor
from the brain for which the criteria for a
high-affinity, stereoselective receptor in brain
tissue had been fulfilled24. Competitive dis-
placement of [3H]CP55940 from its target in
rat brain membranes by cannabinoid agonists
was enantioselective and followed the order
of potency for both Gi-mediated inhibitionof
adenylyl cyclase as well as antinociception
in several rodent models24–27. Later, signal
transduction assays were used to ultimately
deorphanize a 7-transmembrane receptor
now known to be the cannabinoid receptor 1
(CB1; also known as CNR1)28,29.
Discovery of endocannabinoids and CB2
Receptors are mostly activated by endog-
enous molecules, and therefore, there was
a strong reason to look for endogenous
cannabinoids. As ∆9-THC and its related
compounds that bind to the CB1 are lipids,
it was reasonable to assume that any endog-
enous cannabinoids would also be lipids. In
order to isolate putative endogenous can-
nabinoid compounds, the ability of porcine
brain extracts to displace a novel, highly
potent radiolabelled cannabinoid probe,
[3H]HU-243, bound to CB1 was tested in
the Mechoulam laboratory. The fractions
that inhibited the binding of [3H]HU-243 to
the cannabinoid receptor were purified by a
series of chromatographies, which ultimately
led to the generation of a minute amount of
a single compound, an amide of arachidonic
acid — arachidonoyl ethanolamide — which
was named anandamide; this was the first
endocannabinoid to be identified30. The struc-
ture of anandamide (FIG.3) was established
by mass spectrometry, NMR spectroscopy
and by its synthesis30. Anandamide was
found to have inhibitory activity that was
equivalent to that of ∆9-THC and was sub-
sequently shown to have cannabimimetic
activity as it inhibited the twitch response of
isolated mouse vasa deferentia30.
In the meantime, a second receptor, CB2
(also known as CNR2), had been identified
by sequence homology31 and was presumed
to be mainly present in the periphery;
therefore, a search for a ‘peripheral’ endog-
enous agonist was initiated. Using the same
techniques that were used to isolate anan-
damide, it was possible to isolate an ester of
arachidonic acid — 2-arachidonoyl glycerol
(2-AG)32 — from canine intestines (FIG.1).
This compound was unexpectedly found
to bind CB1 and CB2 and to inhibit ade-
nylyl cyclase with a potency similar to that
of 9-THC. 2-AG also shared the ability of
9-THC and anandamide to inhibit electri-
cally evoked contractions of isolated mouse
vasa deferentia; however, it was less potent
than 9-THC32. Following administration
Nature Reviews | Neuroscience
O
OH
Δ9-THC Cannabidiol
O
OH
Cannabinol
OH
HO
O
OH
Δ8-THC Δ6a10a-THC
CP-55940
O
OH
OH
O
OH
OHO
O
OH
OH
OH
HO
Metabolism
Metabolism
11-OH-Δ9-THC
Δ9-THC-11-oic acid
Figure 2 | A major metabolic pathway of Δ9-THC and the structures of some plant and syn
thetic cannabinoids. a | The major psychoactive cannabis constituent, 9-tetrahydrocannabinol
(9-THC), is first metabolized by enzymatic hydroxylation to produce psychoactive 11-hydroxy-
9-THC (11-OH-9-THC) and then by enzymatic oxidation to non-psychoactive9-THC-11-oic
acid,which is stored in fatty tissues as a glucuronide and is slowly released. The glucuronide may
be detected in the urine for several weeks after a single cannabis use. b | The structures of some plant
and synthetic cannabinoids. 9-THC, the plant constituents cannabinol and 8-THC, and synthetic
6a,10a-THC and CP-55940 cause cannabis-type psychoactivity, wherease cannabidiol does not.
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to mice, both anandamide and 2-AG caused
the typical tetrad of effects produced by
9-THC: antinociception, immobility, reduc-
tion of spontaneous activity and lowering of
rectal temperature.Although a few additional
endocannabinoids have been reported, none
of them has been confirmed as a natural
endocannabinoid.
Anandamide is a partial agonist for CB1
and CB2 and shows less relative intrinsic
activity (also known as relative intrinsic
efficacy) and affinity for CB2 than for CB1.
2-AG shows greater potency and efficacy
than anandamide as a CB1 agonist and
greater potency than anandamide as a CB2
agonist33. In addition, it has been found
that both endocannabinoids interact with
certain non-CB1 and non-CB2 receptors
and ion channels33. In the past few years,
lipoxinA4 and a new family of peptides
(known as pepcans) have been reported to
target CB1 as allosteric modulators34,35 and the
peptide hemopressin, which is a putative
brain constituent, has been found to lower
pain via action on a cannabinoid receptor36.
Synthesis of cannabinoid analogues that
have high affinity and specificity for CB2
was achieved in the mid to late 1990s37,38 and
led to the discovery of the role of CB2 in
immunosuppression, neuroprotection and
neuropathic and inflammatory pain. This
consequently led to considerable interest in
developing and investigating CB2-selective
agonists39–43.
Both anandamide and 2-AG are syn-
thesized on demand, often in response to
increased concentration of intracellular
calcium44, and it is now generally accepted
that one important role of these endocan-
nabinoids, although possibly only of 2-AG, is
to function as retrograde synaptic messengers
that can prevent the development of exces-
sive neuronal activity in the central nerv-
ous system and thereby contribute to the
maintenance of homeostasis in both health
and diseas e45. Thus, there is good evidence
that neurotransmitters, such as glutamate,
produce postsynaptic increases in the concen-
tration of intracellular calcium in a manner
that can induce postsynaptic biosynthesis
and release of anandamide or 2-AG into the
synapse. In turn, this induces subsequent
endocannabinoid-induced activation of
presynaptic CB1, which causes an inhibi-
tion of the neuronal release of glutamate,
γ-aminobutyric acid or other neurotransmit-
ters in brain areas that include the cerebral
cortex, hippocampus, ventral tegmental area,
substantia nigra, hypothalamus and cerebel-
lum46–48. There is also evidence that, when
produced postsynaptically in response to
the activation of postsynaptic metabotropic
glutamate receptor 5 (MGLUR5) , ananda-
mide activates post synaptic transient receptor
potential cation channel subfamily V member 1
(TRPV1) channels48. It is also noteworthy
that results obtained from invivo experi-
ments with rats suggest that retrograde 2-AG
signalling that is triggered by the activation of
MGLUR5 can suppress pain sensitivity49. The
endocannabinoid retrograde transport mech-
anism and modulation of synaptic transmis-
sion have not yet been fully elucidated46–48.
Search for antagonist ligands
The holy grail for cannabinoid synthetic
chemists was an antagonist that could block
the effects of ∆9-THC. It seems quite unu-
sual that no natural product or structurally
related analogue emerged to block the can-
nabinoid receptors. Before the advent of
gene knockout techniques, it was difficult to
establish whether a pharmacological effect
was mediated by a receptor if a selective
antagonist for that receptor had not been
developed. Thus, one can imagine the excite-
ment generated at an International Can-
nabinoid Research Society meeting in 1993
when a team of researchers from the French
pharmaceutical company Sanofi Recherche
announced their discovery of an antagonist
for CB1, SR141716A50. This compound was
radiolabelled to investigate receptor pharma-
cology51 and was soon modified to develop
the first ligands for invivo imaging52. The
discovery of an antagonist (SR141716A),
which was in fact subsequently identified
as an inverse agonist, helped to characterize
additional cellular signalling pathways for
CB1 (REFS 50, 51, 53–55). More importantly,
an antagonist could finally be used to iden-
tify animal behaviours that were truly due to
CB1 activation56–58. Indeed, the syndrome of
dependence’ on cannabinoid agonists was
first shown in an animal model after pre-
cipitated withdrawal using SR141716A59,60.
Within a short period of time, industrial
laboratories and academic research groups
reported the synthesis of additional CB1
antagonists and inverse agonists61–64.
The first CB2-selective antagonists
AM630 (also known as iodopravado-
line)and SR144528 emerged in the mid
1990s65,66 and increased the ability to discern
novel actions that could be attributed to
CB2, including actions observed in liver
Kupfer cells67, microglial cells and astro-
cytes68,69 and in the gastrointestinal system70,
among others. Since that time, there has
been considerable progress towards the
development of highly selective and potent
CB2 antagonists41,71.
SR141716A (also known as rimonabant)
is used therapeutically for the treatment of
obesity-related metabolic syndrome compo-
nents, including dyslipidaemia and diabe-
tes72–74. SR141716A was marketed in Europe
but failed to gain approval from the US Food
and Drug Administration. As might be pre-
dicted, a drug that blocks CB1 neuromodula-
tion at synapses for the major stimulatory (in
the case of glutamate) and inhibitory (inthe
case of GABA) transmitters throughout
the brain would be likely to produce multi-
ple ‘off-target’ effects. One such side effect,
which was reported in 2009, was an increase
in reported signs of depression in vulnerable
individuals treated with SR141716A75,76. It
could be argued that the benefit to risk ratio
in a morbidly obese patient population might
mitigate the concerns about depression.
However, the drug was withdrawn from the
market and similar analogues from other
pharmaceutical companies were taken out
of the development pipeline. Nevertheless,
the development of SR141716A by Sanofi–
Aventis can be considered to be a major
contributor to our understanding that CB1
is present and functional in tissues such as
adipose, liver and pancreas under pathologi-
cal conditions of high-fat diet or obesity77.
This new understanding of the role of CB1 in
metabolic regulation has inspired the search
for novel antagonists that fail to gain access to
the brain78,79. An alternative clinical strategy
would be to screen for individuals who might
be most susceptible to the limbic effects of
CB1 antagonists before selecting a treatment
modality80.
Nature Reviews | Neuroscience
N
OH
O
H
O
OH
O
OH
Arachidonoyl ethanolamide
2-Arachidonoyl glycerol
Figure 3 | Structures of the main endocannabi
noids, anandamide and 2‑AG, which bind to
CB1 and CB2 endocannabinoid receptors.
Arachidonoyl ethanolamide (also known as anan-
damide) and 2-arachidonoyl glycerol (2-AG) are
hydrolysed to arachidonic acid by the enzymes
fatty acid amide hydrolase (FAAH) and monoacyl-
glycerol lipase (MAGL), respectively. Blocking
these enzymes with various synthetic com-
pounds leads to increased levels of these
endocannabinoids.
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Endocannabinoid neuropharmacology
The discovery that anandamide and 2-AG
are endocannabinoids prompted research to
identify the biochemical processes that are
responsible for both their biosynthesis and
their metabolism. This research showed that
these two endocannabinoids are synthesized
on demand’ rather than stored, and it iden-
tified biosynthetic and metabolic pathways
for both of them81–83. Thus, it has been dis-
covered that 2-AG is formed from diacylg-
lycerol (DAG) in a process that is catalysed
by sn1-specific DAG lipase-α and lipase-β,
and that the main biosynthetic pathway
for anandamide involves the formation of
N-arachidonoyl phosphatidylethanolamine
(NAPE) from phosphatidylethanolamine
and phosphatidylcholine, which is catalysed
by an as yet uncharacterized calcium-
dependent transacylase enzyme. This is
then followed by the conversion of NAPE to
anandamide in a single step that is catalysed
by NAPE-selective phospholipase D and/
or in two or three steps that are catalysed
by other enzymes. It has also been found
that, following their release, anandamide
and 2-AG are mainly metabolized to ara-
chidonic acid, the major metabolizing
enzymes being fatty acid amide hydrolase
(FAAH) for anandamide and mono-
acylglycerol lipase (MAGL) for 2-AG81,82.
Other endocannabinoid-metabolizin g
enzymes include FAAH-2 for ananda-
mide, α,β-hydrolase domain-containing 6
(ABDH6) and ABDH12 for 2-AG, and cyto-
chrome P450 enzymes, lipoxygenases and
cyclooxygenase2 for both of these endocan-
nabinoids81,82. The physiological relevance
of the lipoxygenase and cyclooxygenase
derivatives of anandamide and 2-AG is not
yet clear. It is also noteworthy that ananda-
mide and 2-AG can undergo cellular uptake
following their release, although whether
this process is mediated by a transporter is
currently unclear81,82.
It is now recognized that,although engi-
neering exogenous cannabinoids provided
insights into receptor usage and linked func-
tional events, the intracellular and extracel-
lular actions and fate of endocannabinoids
versus those of exogenously introduced
cannabinoids may differ and have different
physiological consequences 33,44. It is also
recognized that many cannabinoid receptor
ligands also interact with a wide range of
non-cannabinoid receptor targets and that,
irrespective of whether they are endogenous,
synthetic or plant cannabinoids, the pharma-
cological profiles of these compounds often
vary considerably from each other33,44.
The endocannabinoid receptors, the
endocannabinoids and their biosynthetic and
biodegrading enzymes constitute what has
come to be known as the endocannabinoid
system, the discovery of which prompted a
search for its physiological and pathophysi-
ological roles. This search revealed that there
are several disorders in which endocan-
nabinoids are released to their receptors in
an ‘autoprotective’ manner that ameliorates
unwanted effects of these disorders82–84. It
also raised the possibility that increasing
extracellular levels of a released endocan-
nabinoid by inhibiting metabolizing enzymes
such as FAAH or MAGL, or by inhibiting
the cellular uptake of anandamide, might
prove to be an effective therapeutic strategy
to manage some of these disorders, which
include multiple sclerosis, Parkinson’s dis-
ease, schizophrenia, hypertension, inflam-
matory bowel diseases, pruritus, Alzheimer’s
disease, depression, obsessive compulsive
disorder and cancer82–84.
The discovery of the endocannabinoid
system also led to a reinvestigation of the
interactions of plant and synthetic cannabi-
noids with this system and other biochemical
entities. As a result, evidence has emerged
that 9-THC targets receptors other than CB1
(REFS85–87). For example, at submicromolar
concentrations, 9-THC has also been found
to have several effects: first, it has been found
to activate CB2, albeit with less efficacy than
it activates CB1 (REF.88); second, it has been
found to activate the deorphanized GPCRs
GPR18 (REF.89) and GPR55 (REF.33), the
cation channels TRPA1 and TRPV2 (REFS90)
and the nuclear receptor peroxisome prolifer-
ator-activated receptor-γ (PPARγ)33; third, it
has been found to block the activation both of
5-hydroxytryptamine 3 (5HT3) ligand-gated
ion channels33,85 and of TRPM8 cation chan-
nels90; and, last, it has been found to enhance
the activation both of α1 subunits and α1β1
dimers of human glycine ligand-gated ion
channels and of native glycine receptors in
rat isolated ventral tegmental area neurons33.
There have also been reports that submicro-
molar concentrations of 9-THC can inhibit
the enzyme lysophosphatidylcholine acyl
transferase11, that it can increase the activity
Glossary
Affinity
The potency with which a compound binds to a particular
receptor; the higher the affinity of the compound, the
lower the concentration at which it achieves a given level of
receptor occupancy.
Agonists
Compounds that can activate pharmacological receptors; a
full agonist is more potent than a partial agonist and so
usually produces a greater maximum functional response.
Allosteric modulators
Drugs that can act on an allosteric site of a receptor to
increase or to reduce the ability of an agonist or an inverse
agonist to induce a functional response when it targets a
different (orthosteric) site on the same receptor.
Antagonist
A compound that can bind to, but cannot activate, a
receptor by targeting its orthosteric site and that can
therefore prevent both drug-induced agonism and
drug-induced inverse agonism at this receptor.
Antinociception
Another term for pain relief.
Apoptosis
A process of programmed cell death that usually has
advantageous consequences.
Catalepsy
A condition that is characterized by immobility and
muscular rigidity.
Endocannabinoid
An endogenous compound that can directly activate or
block cannabinoid CB1 and/or CB2 or that can act as a
positive or negative allosteric modulator to increase or to
reduce responses of CB1 and/or CB2 to direct agonists or
inverse agonists.
G protein-coupled receptor
(GPCR). A seven-transmembrane domain receptor that
induces G-protein-mediated activation of intracellular
signal transduction pathways when occupied by an agonist.
Hashish
A cannabis-derived preparation that consists mostly of
dried cannabis resin.
Hypokinesia
A condition that is characterized by decreased bodily
movement.
Inverse agonist
A compound that binds to a receptor in a manner that
induces a pharmacological response opposite to the
response that is induced by an agonist for the same
receptor.
Relative intrinsic activity
The relative ability of drug–receptor complexes to produce
maximum functional responses; a high-efficacy agonist
needs to occupy fewer receptors to produce a maximal
response than a low-efficacy agonist (also known as a
partial agonist).
Retrograde synaptic messengers
Compounds that are released by a postsynaptic dendrite
or cell body, but that act presynaptically — for example, to
influence the release of a transmitter.
Structure–activity relationship
(SAR). The relationship between the pharmacological
activity of compounds and their chemical structures.
Transient receptor potential cation channel
subfamily V member 1
(TRPV1). A member of a superfamily of transmembrane
cation channels; it was previously known as vanilloid
receptor 1.
PERSPECTIVES
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© 2014 Macmillan Publishers Limited. All rights reserved
of phospholipase C, which can catalyse the
production of DAG and phospholipase A2
(REF.11) and that it can both inhibit the uptake
of adenosine by cultured microglia and mac-
rophages and affect the synaptosomal uptake
of 5-hydroxytryptamine (it inhibits this pro-
cess), of noradrenaline (it enhances this pro-
cess) and of dopamine (it both enhances and
inhibits this process)85,87. In addition, at higher
concentrations, 9-THC has been found to
affect several other such pharmacological
targets85,87. For example, at concentrations
between 1 µM and 10 µM, it has been reported
to enhance the activation of β-adrenoceptors,
to function as a negative allosteric modulator
of µ- and δ-opioid receptors, to activate the
cation channels TRPV3 and TRPV4 and to
inhibit T-type calcium (Cav3) and potassium
(Kv1.2) voltage-gated ion channels, as well as
conductance in Na+ voltage-gated ion chan-
nels. In this concentration range, 9-THC
has also been reported to inhibit the enzymes
lipoxygenase, Na+–K+-ATPase and monoam-
ine oxidase, as well as the cytochrome P450
enzymes CYP1A1, CYP1A2, CYP2B6 and
CYP2C9, to inhibit noradrenaline-induced
melatonin biosynthesis, and to activate or to
inhibit Mg2+-ATPase85,87.
Perspectives
There has been much progress in our under-
standing of the plant cannabinoids and of
CB1 and CB2. We have identified endogenous
lipid mediators that act on these receptors to
regulate multiple pathways of cellular signal-
ling. We have discovered synthetic agonists
and antagonists for these receptors as well as
allosteric modulators of CB1. However, there
is still much more knowledge to be gained
and challenges to be met in the fields of can-
nabinoid receptor neuroscience, pharmacol-
ogy, molecular biology and cannabinoid
medicine.
We now need to understand how the
endocannabinoid receptors interact with
other proteins in complexes that regulate dif-
ferentiated functions both at the cell surface
and in intracellular organelles, particularly in
the brain91–93.
Dozens of endogenous molecules, with
structures that resemble those of the endo-
cannabinoids, have been discovered in the
brain94,95. The activity of most of these mol-
ecules is not known. Some of those that have
been investigated show activities that have
therapeutic potential; for example, arachi-
donoyl serine is a vasodilator96 and is neu-
roprotective after brain injury as it reduces
apoptosis97. It leads to proliferation of neural
progenitor cells invitro and maintains these
cells in an undifferentiated state invitro and
invivo. Although it does not bind to CB1 and
CB2, its activity is blocked by CB2 antago-
nists98. This raises questions, such as what is
the relationship of such endocannabinoid-like
compounds to the endocannabinoid system
and what are the physiological roles of these
molecules in the brain?
Pucci etal.99 have investigated the possible
epigenetic regulation of skin differentia-
tion genes by phytocannabinoids99. CBD
was found to increase DNA methylation of
the keratin 10 gene. Remarkably, CBD also
reduced keratin 10 mRNA levels by a CB1-
dependent mechanism. Thus, in this system,
CBD is apparently a transcriptional repressor
that can control cell proliferation and dif-
ferentiation. As anandamide has also been
found to have epigenetic properties100, it is
of interest to determine the extent, if any, of
transcriptional control by endocannabinoids
by epigenetic mechanisms.
Although various methods have been
used to enhance endocannabinoid levels
invivo (even in patients)82,101, neither anan-
damide nor 2-AG have been administered to
humans. In addition, only a small number of
clinical studies have been carried out using
plant cannabinoids. A notable exception is
the recent successful clinical trial using CBD
in schizophrenic patients101. Although it is
widely mentioned in the general media that
cannabis with a high concentration of CBD
is therapeutic in paediatric epilepsy and that
‘medical marijuana’ is indeed of value in
such cases102, there have not been any recent
clinical trials reported, although several such
trials are ongoing (an anti-epileptic trial of
CBD in adults was reported 34years ago103).
In a recent review, Pacher and Kunos84
suggested that “modulating endocannabi-
noid system activity may have therapeutic
potential in almost all diseases affecting
humans”. They supported this strong state-
ment with a long list of examples, although
these examples were mostly obtained
invitro or from inv ivo experiments in ani-
mals84. If this summary of effects is shown
to reflect actions in human patients, is the
endocannabinoid system going to bring a
revolution in therapy? This might be the
case as investigators are now able to target
multiple cell-specific synthetic and biotrans-
formation enzyme pathways that can adjust
the levels of endocannabinoid ligands with
some degree of tissue selectivity. In addi-
tion, aside from the agonist and antagonist
ligands for cannabinoid receptors, research-
ers can now target cell type-specific allos-
teric modulators and receptor-associated
proteins. Thus, there is great promise for the
future of cannabinoid research.
Raphael Mechoulam is at the Institute for Drug
Research, Medical Faculty, Hebrew University,
Jerusalem, 91120, Israel.
Lumír O. Hanuš is at the Institute for Drug Research,
Medical Faculty, Hebrew University, Jerusalem,
91120, Israel.
Roger Pertwee is at the Institute of Medical Sciences,
University of Aberdeen, Aberdeen AB25 2ZD,
Scotland, UK.
Allyn C. Howlett is at the Department of Physiology
and Pharmacology, Wake Forest University Health
Sciences, One Medical Center Blvd, Winston-Salem,
North Carolina 27157, USA.
Correspondence to R.M.
e-mail: mechou@cc.huji.ac.il
doi:10.1038/nrn3811
Published online 15 October 2014
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Acknowledgements
Research in the laboratory of R.M. was supported by the Kes-
sler Family Foundation, Boston, USA, and by a grant from US
National Institute on Drug Abuse (NIDA), DA-9789. The
research of R.P. was supported by NIDA grants DA-3934,
DA-9789 and DA-3672 and GW Pharmaceuticals and the
research of A.H. was supported by NIDA grant DA-3690.
Competing interests statement
The authors declare no competing interests.
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... Previous systematic reviews have been limited in their coverage of all relevant diseases, but most importantly primarily ignored the fact that medical cannabinoid products-a term that encompasses all plant-derived and synthetic derivatives-differ in their pharmacology [1][2][3][4][5]. The synthetic cannabinoids dronabinol, which is ( −)-trans-Δ 9 -tetrahydrocannabinol (THC) (Marinol ® and Syndros ® ), and nabilone-a synthetic cannabinoid with structural similarities to THC (Cesamet ® ), are partial agonists at the cannabinoid receptor 1 (CB1) and with somehow lower affinity at CB2 receptors [6]. Both cannabinoids have indications as appetite stimulants, antiemetics, cannabis addiction, sleep apnea and analgesics and are approved by the FDA for HIV/AIDS-induced loss of appetite and chemotherapy-induced nausea and vomiting. ...
... Previous SRs and meta-analyses on cannabinoids [1][2][3][4][5] (and many others) did not consider, or only considered via sensitivity analysis, that medical cannabinoids and medical plant-derived cannabis products differ largely in their pharmacological mode of action [6][7][8][9] and pharmacokinetics [165]. For the first time, we provide pharmacology-based comparative systematic results for dronabinol, nabilone, CBD and nabiximols for all relevant medical indications. ...
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Full-text available
Background Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and meta-analyses of medical cannabinoids for efficacy, retention and adverse events. Methods We systematically reviewed (registered at PROSPERO: CRD42021229932) eight databases for randomized controlled trials (RCTs) of dronabinol, nabilone, cannabidiol and nabiximols for chronic pain, spasticity, nausea /vomiting, appetite, ALS, irritable bowel syndrome, MS, Chorea Huntington, epilepsy, dystonia, Parkinsonism, glaucoma, ADHD, anorexia nervosa, anxiety, dementia, depression, schizophrenia, PTSD, sleeping disorders, SUD and Tourette. Main outcomes and measures included patient-relevant/disease-specific outcomes, retention and adverse events. Data were calculated as standardized mean difference (SMD) and ORs with confidence intervals (CI) via random effects. Evidence quality was assessed by the Cochrane Risk of Bias and GRADE tools. Results In total, 152 RCTs (12,123 participants) were analysed according to the type of the cannabinoid, outcome and comparator used, resulting in 84 comparisons. Significant therapeutic effects of medical cannabinoids show a large variability in the grade of evidence that depends on the type of cannabinoid. CBD has a significant therapeutic effect for epilepsy (SMD − 0.5[CI − 0.62, − 0.38] high grade) and Parkinsonism (− 0.41[CI − 0.75, − 0.08] moderate grade). There is moderate evidence for dronabinol for chronic pain (− 0.31[CI − 0.46, − 0.15]), appetite (− 0.51[CI − 0.87, − 0.15]) and Tourette (− 1.01[CI − 1.58, − 0.44]) and moderate evidence for nabiximols on chronic pain (− 0.25[− 0.37, − 0.14]), spasticity (− 0.36[CI − 0.54, − 0.19]), sleep (− 0.24[CI − 0.35, − 0.14]) and SUDs (− 0.48[CI − 0.92, − 0.04]). All other significant therapeutic effects have either low, very low, or even no grade of evidence. Cannabinoids produce different adverse events, and there is low to moderate grade of evidence for this conclusion depending on the type of cannabinoid. Conclusions Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.
... Consequently, there is a need for alternative front-line and adjuvant therapeutics. Extracts from the plant Cannabis sativa are thought to have potential in treating several conditions such as pain [3]. Cannabis contains hundreds of phytocannabinoids, including the major psychoactive constituent ∆9-tetrahydrocannabinol (THC), and other non-psychoactive constituents such as cannabidiol (CBD). ...
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(1) Background: The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduce allodynia in various animal models of neuropathic pain. Unfortunately, THC-containing drugs also produce substantial side-effects when administered systemically. We examined the effectiveness of targeted spinal delivery of these cannabis constituents, alone and in combination. (2) Methods: The effect of acute intrathecal drug delivery on allodynia and common cannabinoid-like side-effects was examined in a mouse chronic constriction injury (CCI) model of neuropathic pain. (3) Results: intrathecal THC and CBD produced dose-dependent reductions in mechanical and cold allodynia. In a 1:1 combination, they synergistically reduced mechanical and cold allodynia, with a two-fold increase in potency compared to their predicted additive effect. Neither THC, CBD nor combination THC:CBD produced any cannabis-like side-effects at equivalent doses. The anti-allodynic effects of THC were abolished and partly reduced by cannabinoid CB1 and CB2 receptor antagonists AM281 and AM630, respectively. The anti-allodynic effects of CBD were partly reduced by AM630. (4) Conclusions: these findings indicate that intrathecal THC and CBD, individually and in combination, could provide a safe and effective treatment for nerve injury induced neuropathic pain.
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The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.
Chapter
The growth, distribution, and use of Cannabis sativa (cannabis) have been tightly restricted for decades due to the therapeutic and psychoactive molecules it produces. Despite long-standing cultivation, scientific research on cannabis has been limited, with past efforts to breed and improve this crop largely supported by an illegal global economy. The easing of legal restrictions and the rapid growth of genomic tools and biotechnology have accelerated research and targeted trait development in cannabis. These advances have enabled the establishment of regulatory standards that ensure safe products for human consumption, and supported efforts to bioengineer cannabinoid production for an eco-conscious future. This chapter discusses societal and scientific influences on the cannabis plant, with a focus on the impact of genomics and biotechnology on cannabis research, and the legal and environmental challenges faced by the future of this industry and its impact on the global bioeconomy.
Chapter
Endocannabinoids (eCBs) are endogenous lipids able to bind to cannabinoid receptors, the primary molecular targets of the cannabis (Cannabis sativa) active principle Δ9-tetrahydrocannabinol. During the last 20 years, several N-acylethanolamines and acylesters have been shown to act as eCBs, and a complex array of receptors, metabolic enzymes, and transporters (that altogether form the so-called “eCB system”) has been shown to finely tune their manifold biological activities. It appears now urgent to develop methods and protocols that allow to assay in a specific and quantitative manner the distinct components of the eCB system and that can properly localize them within the cell. A brief overview of eCBs and of the proteins that bind, transport, and metabolize these lipids is presented here, in orderto put in a better perspective, the relevance of methodologies that help to disclose molecular details of eCB signaling in health and disease. Proper methodological approaches form also the basis for a more rationale and effective drug design and therapeutic strategy to combat human disorders.Key wordsAnandamide2-ArachidonoylglycerolEnzyme assaysImmunochemical assaysIntracellular traffickingLocalizationMetabolic routesOxidative pathwaysReceptor binding assaysSignal transduction
Chapter
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Chapter
Body homeostasis is fully dependent on the different physiological systems working together in an orchestrated way. Different hormones, autacoids, and other bioactive molecules are known to play a role in the modulation of such events, either during a normal response to different stimuli or upon any harmful condition that will impact tissue or organ. The kidneys are very important for whole body homeostasis as they are responsible for the control of blood pressure, maintenance of the water compartments volume and composition, detoxification, reabsorption, pH regulation, and even some hormone production. Here we will discuss the ability of cannabinoids (phyto- or endocannabinoids) as modulators of renal physiology, which may open new perspectives for the development of new therapeutic drugs or the discovery of new patterns of endocannabinoids that may be explored as biomarkers for nephropathies or kidney repair toward precision medicine initiatives.
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Endocannabinoids (eCBs) are lipid neuromodulators that suppress neurotransmitter release, reduce postsynaptic excitability, activate astrocyte signaling, and control cellular respiration. Here, we describe canonical and emerging eCB signaling modes and aim to link adaptations in these signaling systems to pathological states. Adaptations in eCB signaling systems have been identified in a variety of biobehavioral and physiological process relevant to neuropsychiatric disease states including stress-related disorders, epilepsy, developmental disorders, obesity, and substance use disorders. These insights have enhanced our understanding of the pathophysiology of neurological and psychiatric disorders and are contributing to the ongoing development of eCB-targeting therapeutics. We suggest future studies aimed at illuminating how adaptations in canonical as well as emerging cellular and synaptic modes of eCB signaling contribute to disease pathophysiology or resilience could further advance these novel treatment approaches.
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Δ9-THC (the main active compound from Cannabis sativa) and related cannabinoids have been used as drugs of abuse and as medications. They induce a complex set of emotional responses in humans and experimental animals, consisting of either anxiolysis or heightened anxiety. These discrepant effects pose a major challenge for data reproducibility and for developing new cannabinoid-based medicines. In this study, we review and analyze previous data on cannabinoids and anxiety-like behavior in experimental animals. Systematic review and meta-analysis on the effects of type-1 cannabinoid receptor agonists (full or partial, selective or not) in rodents exposed to the elevated plus maze, a widely used test of anxiety-like behavior. Cannabinoids tend to reduce anxiety-like behavior if administered at low doses. THC effects are moderated by the dose factor, with anxiolytic- and anxiogenic-like effects occurring at low-dose (0.075-1 mg/kg) and high-dose (1-10 mg/kg) ranges, respectively. However, some studies report no effect at all regardless of the dose tested. Finally, motor impairment represents a potential confounding factor when high doses are administered. The present analysis may contribute to elucidate the experimental factors underlying cannabinoid effects on anxiety-like behavior and facilitate data reproducibility in future studies.
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Complementary genetic and pharmacological approaches to inhibit the monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), the primary hydrolytic enzymes of the respective endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), enable the exploration of potential therapeutic applications and physiological roles of these enzymes. Complete and simultaneous inhibition of both FAAH and MAGL produces greatly enhanced cannabimimetic responses, including increased antinociception, and other cannabimimetic effects, far beyond inhibition of either enzyme alone. While CB1 receptor function is maintained following chronic FAAH inactivation, prolonged excessive elevation of brain 2-AG levels, via MAGL inhibition, elicits both behavioral and molecular signs of cannabinoid tolerance and dependence. Here, we evaluated the consequences of high dose of the MAGL inhibitor, JZL184 (40 mg/kg) given acutely or for six days in FAAH (-/-) and (+/+) mice. While acute administration of JZL184 to FAAH (-/-) mice enhanced the magnitude of a subset of cannabimimetic responses, repeated JZL184 treatment led to tolerance to its antinociceptive effects, cross-tolerance to the pharmacological effects of THC, decreases in CB1 receptor agonist stimulated [(35)S]GTPγS binding, and dependence as indicated by rimonabant-precipitated withdrawal behaviors, regardless of genotype. Together, these data suggest that simultaneous elevation of both endocannabinoids elicits enhanced cannabimimetic activity, but MAGL inhibition drives CB1 receptor functional tolerance and cannabinoid dependence.
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CB1 receptor antagonists were among the most promising drug targets in the last decade. They have been explored and found to be effective as therapeutic agents for obesity and related cardiometabolic problems; however, use of rimonabant, the first marketed CB1 receptor antagonist, has been suspended because of its anxiogenic and depressogenic side effects. Because some other antiobesity drugs, like dexfenfluramine or sibutramine, were also suspended, the unmet need for drugs that reduce body weight became enormous. One approach that emerged was the use of CB1 receptor antagonists that poorly cross the blood brain barrier, the second, the development of neutral antagonists instead of inverse agonists, and the third, use of personalized medicine, namely the selection of the patient population without psychiatric side effects. In this review, we dissect the peripheral and central mechanisms involved in the effects of CB1 receptor antagonists and argue that central mechanisms are more or less involved in most cardiometabolic therapeutic effects and thus, among patients with unsatisfactory therapeutic response to compounds with peripheral action, centrally acting antagonists may be needed. An analysis of pharmacogenetic factors may help to identify persons who are at no or low risk for psychiatric adverse effects. Here, we present the models and identify molecular mechanisms and receptors involved in the effects of stress-, anxiety- and depression-related neurocircuitries sensitive to CB1 receptor antagonists, like the serotonergic, noradrenergic and dopaminergic systems, which are not only regulated by CB1 receptors, but also regulate the synthesis of the endocannabinoid 2-arachidonoyl-glycerol. © 2012 The Authors. Acta Physiologica
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Background and objectives: Many patients with post-traumatic stress disorder (PTSD) achieve but partial remission with current treatments. Patients with unremitted PTSD show high rates of substance abuse. Marijuana is often used as compassion add-on therapy for treatment-resistant PTSD. This open-label study evaluates the tolerance and safety of orally absorbable Δ(9)-tetrahydrocannabinol (THC) for chronic PTSD. Methods: Ten outpatients with chronic PTSD, on stable medication, received 5 mg of Δ(9)-THC twice a day as add-on treatment. Results: There were mild adverse effects in three patients, none of which led to treatment discontinuation. The intervention caused a statistically significant improvement in global symptom severity, sleep quality, frequency of nightmares, and PTSD hyperarousal symptoms. Conclusions: Orally absorbable Δ(9)-THC was safe and well tolerated by patients with chronic PTSD.
Article
N-acylethanolamine acid amidase (NAAA) is a cysteine amidase that hydrolyzes saturated or monounsaturated fatty acid ethanolamides, such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA has been shown to exert analgesic and anti-inflammatory effects by engaging peroxisome proliferator-activated receptor-α. Like other fatty acid ethanolamides, PEA is not stored in cells, but produced on demand from cell membrane precursors, and its actions are terminated by intracellular hydrolysis by either fatty acid amide hydrolase or NAAA. Endogenous levels of PEA and OEA have been shown to decrease during inflammation. Modulation of the tissue levels of PEA by inhibition of enzymes responsible for the breakdown of this lipid mediator may represent therefore a new therapeutic strategy for the treatment of pain and inflammation. While a large number of inhibitors of fatty acid amide hydrolase have been discovered, few compounds have been reported to inhibit NAAA activity. Here, we describe the most representative NAAA inhibitors and briefly highlight their pharmacological profile. A recent study has shown that a NAAA inhibitor attenuated heat hyperalgesia and mechanical allodynia caused by local inflammation or nerve damage in animal models of pain and inflammation. This finding encourages further exploration of the pharmacology of NAAA inhibitors.
Article
Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) [Sativex(®)] is an oromucosal spray formulation that contains principally THC and CBD at an approximately 1:1 fixed ratio, derived from cloned Cannabis sativa L. plants. The main active substance, THC, acts as a partial agonist at human cannabinoid receptors (CB1 and CB2), and thus, may modulate the effects of excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) neurotransmitters. THC/CBD is approved in a number of countries, including Germany and the UK, as an add-on treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. In the largest multinational clinical trial that evaluated the approved THC/CBD regimen in this population, 12 weeks' double-blind treatment with THC/CBD significantly reduced spasticity severity (primary endpoint) compared with placebo in patients who achieved a clinically significant improvement in spasticity after 4 weeks' single-blind THC/CBD treatment, as assessed by a patient-rated numerical rating scale. A significantly greater proportion of THC/CBD than placebo recipients achieved a ≥30 % reduction (a clinically relevant reduction) in spasticity severity. The efficacy of THC/CBD has been also shown in at least one everyday clinical practice study (MOVE 2). THC/CBD was generally well tolerated in clinical trials. Dizziness and fatigue were reported most frequently during the first 4 weeks of treatment and resolved within a few days even with continued treatment. Thus, add-on THC/CBD is a useful symptomatic treatment option for its approved indication.
Article
Primary sensory afferents and their neighboring host-defense cells are a rich source of lipid-derived mediators that contribute to the sensation of pain caused by tissue damage and inflammation. But an increasing number of lipid molecules have been shown to act in an opposite way, to suppress the inflammatory process, restore homeostasis in damaged tissues and attenuate pain sensitivity by regulating neural pathways that transmit nociceptive signals from the periphery of the body to the CNS. Here we review the molecular and cellular mechanisms that contribute to the modulatory actions of lipid mediators in peripheral nociceptive signaling.