ArticlePDF AvailableLiterature Review

Clinical Endocannabinoid Deficiency (CECD): Can this Concept Explain Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and other Treatment-Resistant Conditions?

Authors:
  • CReDO Science

Abstract

This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.
30
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Neuroendocrinology Letters Nos.1/2, Feb-Apr Vol.25, 2004
Copyright © 2004 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Clinical Endocannabinoid Deciency (CECD):
Can this Concept Explain Therapeutic Benets of Cannabis in
Migraine, Fibromyalgia, Irritable Bowel Syndrome and other
Treatment-Resistant Conditions?
Ethan B. Russo
Senior Medical Advisor, GW Pharmaceuticals, 2235 Wylie Avenue, Missoula, MT 59802, USA
Correspondence to: Ethan B. Russo, M.D.
Senior Medical Advisor, GW Pharmaceuticals
2235 Wylie Avenue
Missoula, MT 59802, USA
VOICE: +1 406-542-0151
FAX: +1 406-542-0158
EMAIL: erusso@montanadsl.net
Submitted: December 1, 2003
Accepted: February 2, 2004
Key words:
cannabis; cannabinoids; medical marijuana; analgesia; migraine;
headache; irritable bowel syndrome; bromyalgia; causalgia;
allodynia; THC; CBD
Neuroendocrinol Lett 2004; 25(1/2):31–39 NEL251204R02 Copyright © Neuroendocrinology Letters www.nel.edu
Abstract
OBJECTIVES
: This study examines the concept of clinical endocannabinoid de-
ciency (CECD), and the prospect that it could underlie the pathophysiology of
migraine, bromyalgia, irritable bowel syndrome, and other functional condi-
tions alleviated by clinical cannabis.
METHODS: Available literature was reviewed, and literature searches pursued
via the National Library of Medicine database and other resources.
RESULTS: Migraine has numerous relationships to endocannabinoid func-
tion. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors
supporting therapeutic efcacy in acute and preventive migraine treatment.
Cannabinoids also demonstrate dopamine-blocking and anti-inammatory
effects. AEA is tonically active in the periaqueductal gray matter, a migraine
generator. THC modulates glutamatergic neurotransmission via NMDA recep-
tors. Fibromyalgia is now conceived as a central sensitization state with sec-
ondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to
block spinal, peripheral and gastrointestinal mechanisms that promote pain in
headache, bromyalgia, IBS and related disorders. The past and potential clini-
cal utility of cannabis-based medicines in their treatment is discussed, as are
further suggestions for experimental investigation of CECD via CSF examina-
tion and neuro-imaging.
CONCLUSION: Migraine, bromyalgia, IBS and related conditions display
common clinical, biochemical and pathophysiological patterns that suggest an
underlying clinical endocannabinoid deciency that may be suitably treated
with cannabinoid medicines.
R E V I E W A R T I C L E
32
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
33
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
Abbreviations
AEA: arachidonylethanolamide, anandamide
2-AG: 2-arachidonylglycerol
CB
1
: cannabinoid 1 receptor
CBD: cannabidiol
CECD: clinical endocannabinoid deciency
CGRP: calcitonin gene-related peptide
CNS: central nervous system
CRP: complex regional pain
ECT: electroconvulsive therapy
FAAH: fatty acid amide hydrolase
fMRI: functional magnetic resonance imaging
5-HT: 5-hydroxytryptamine, serotonin
GI: gastrointestinal
IBS: irritable bowel syndrome
NMDA: N-methyl-d-aspartate
PAG: periaqueductal gray
PET: positron emission tomography
PTSD: post-traumatic stress disorder
RSD: reex sympathetic dystrophy
THC:
9
-tetrahydrocannabinol
TMJ: temporomandibular joint
VR
1
: vanilloid 1 receptor
Introduction
In the initial lines of his 1895 work, Project for a
Scientic Psychology, Sigmund Freud stated [1] (p.
295), “The intention is to furnish a psychology that
shall be a natural science: that is, to represent psy-
chical processes as quantitatively determinate states
of speciable material particles, thus making those
processes perspicuous and free from contradiction.”
Freud was frustrated in this effort, and found that
available science at the twilight of the 19
th
century was
not capable of providing biochemical explanations for
cerebral processes, leading him to pursue psychody-
namic theory alternatively.
At the dawn of the 21
st
century, despite astounding
progress in psychopharmacology, medicine remains
challenged in its attempts to understand and success-
fully treat a large number of recalcitrant syndromes,
noteworthy among them, migraine, bromyalgia, and
irritable bowel syndrome (IBS). For many physicians
these problematic entities suggest a psychosomatic
or “functional” etiology that remains shorthand for
a diagnosis where our biochemical understanding and
therapeutic vigor fall short of the mark.
In the last fteen years, however, the discovery
of the endogenous cannabinoid (endocannabinoid)
system [2] has provided new insights into a neuro-
modulatory scheme that portends to provide better
explanations of, and treatments for, a wide variety of
previously intractable disorders, particularly painful
conditions (reviewed in [3; 4]).
After all, for each neurotransmitter system there
are pathological conditions attributable to its de-
ciency: dementia in Alzheimer disease due to loss of
acetylcholine activity, Parkinsonism due to dopamine
deciency, depression secondary to lowered levels of
serotonin, norepinephrine or other amines, etc. Should
the situation be any different for the endocannabinoid
system, whose receptor density is in fact greater than
many of the others? This article will explore that ques-
tion and propose a concept rst articulated in prior
publications [5; 6], that a clinical endocannabinoid de-
ciency (CECD), whether congenital or acquired may
help to explain the pathophysiology of certain diagnos-
tic pitfalls, especially those characterized by hyperal-
gesia, and thereby provide a basis for their treatment
with cannabinoid medicines.
Mechanisms of action of cannabis and THC have
recently been elucidated with the discovery of canna-
binoid receptors and an endogenous ligand, arachido-
nylethanolamide, nicknamed anandamide, from the
Sanskrit word ananda, or “bliss” [7]. Anandamide
(AEA) inhibits cyclic AMP mediated through G-pro-
tein coupling in target cells, which cluster in nocicep-
tive areas of the CNS [8]. Preliminary tests of its phar-
macological action and behavioral activity support
similarity of AEA to THC [9], and both entities are
partial agonists at the CB
1
receptor. Pertwee [4] has
examined the pharmacology of cannabinoid receptors
and pain in detail.
Methods
Available literature was reviewed, and literature
searches pursued via the National Library of Medicine
database and other Internet resources.
Results
Migraine
Migraine is a public health issue of astounding soci-
etal cost. There are an estimated 23 million sufferers in
the USA [10], with an economic impact of $1.2 to $17.2
billion annually [11]. The neurochemistry of migraine
is among the most complex of any human malady, and
its relation to cannabinoid mechanisms has been ex-
amined previously in brief [12] and in depth [5].
Serotonergic pathways are considered integral to
migraine pathogenesis and treatment. Numerous
points of intersection with cannabinoid mechanisms
are evident: THC inhibits serotonin release from the
platelets of human migraineurs [13]; THC stimulates
5-HT synthesis, inhibits synaptosomal uptake, and
promotes its release [14]; AEA and CB
1
agonists
inhibit rat serotonin type 3 (5-HT
3
) receptors [15] in-
volved in emetic and pain responses. Additionally, AEA
produces an 89% relative potentiation of the 5-HT
1A
receptor response, and a 36% inhibition of the 5-HT
2A
receptor response [16]. Another endocannabinoid, 2-
arachidonylglycerol (2-AG) inhibited 5-HT
2A
by 28%.
Recently, mild but signicant similar activity on 5-
HT
2A
has been demonstrated for cannabidiol [17], and
cannabis terpenoids [18]. Higher concentrations of
anandamide decreased serotonin and ketanserin bind-
ing (the latter being a 5-HT
2A
antagonist) [19]. These
observations support putative efcacy of therapeutic
cannabinoids in acute migraine (agonistic activity at
5-HT
1A
or D) and in its prophylactic treatment (an-
tagonistic activity at 5-HT
2A
) [20].
The importance of dopaminergic mechanisms in
migraine has also been explored [21]. 6-hydroxydo-
pamine, which causes degeneration of catecholamine
Ethan B. Russo
32
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
33
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
terminals, blocked THC antinociception [22]. AEA
stimulates nitric oxide formation through inhibition of
presynaptic dopamine release [23]. Dopamine block-
ing and modulatory effects of cannabis and THC have
been demonstrated in studies of Tourette syndrome
[24; 25], and schizophrenia in Germany [26], suggest-
ing that THC may similarly modulate dopaminergic
imbalances in headache.
Inammatory mechanisms affected by cannabis
are legion (reviewed [27–31]. THC and cannabinoids
inhibit prostaglandin E-2 synthesis [32]; smoked can-
nabis reduces platelet aggregation [33]; THC demon-
strated an oral potency as an anti-inammatory 20
times that of aspirin and twice that of hydrocortisone
[34], and cannabidiol (CBD) inhibited both cyclooxy-
genase and lipoxygenase. Similarly, anandamide and
metabolites are substrates for brain lipoxygenase [35].
Opiates, cannabinoids and eicosanoids signal through
common nitric acid coupling [36], while THC blocks
the conversion of arachidonate into metabolites de-
rived by cyclooxygenase activity, and stimulates lipox-
ygenase, promoting down-regulation of inammation.
CNS beta-endorphin levels are depleted during mi-
graine attacks [37], but THC experimentally increases
them [38]. THC additionally regulates substance P
and enkephalin mRNA levels in the basal ganglia
[39]. THC affects an analgesic brainstem circuit in
the rostral ventromedial medulla that interacts with
opiate pathways [40], mediating antinociception after
activation of neurons in the midbrain periaqueductal
grey matter (PAG), a putative migraine generator
area [41], wherein THC and other cannabinoids are
antinociceptive [42]. The PAG is an integral processor
of ascending and descending pain pathways, fear and
anxiety [43]. Additional support is provided by studies
demonstrating tritiated sumatriptan binding in hu-
man PAG [44], and that THC administration elevates
proenkephalin gene expression in the PAG [45]. Most
compelling is data supporting tonic activity of anan-
damide in the PAG with production of analgesia, and
hyperalgesia upon cannabinoid antagonism [46].
Cannabinoids may represent a therapeutic ad-
vantage over opiates, particularly in treatment of
neuropathic pain [47]. Opiates commonly aggravate
migraine or even provoke its appearance [48], as
observed therapeutic doses of morphine failed to al-
leviate acute attack and increased hyperalgesia in
migraineurs during inter-ictal periods.
A trigeminovascular system has long been impli-
cated as integral to the pain, inammation and sec-
ondary vascular effects of migraine, linked through
the NMDA/glutamate system [49]. Cannabinoid
agonists inhibit voltage-gated calcium channels, and
activate potassium channels to produce presynaptic
inhibition of glutamate release [50], without dissocia-
tive effects noted with other NMDA inhibitors, such
as ketamine. Subsequently, THC was shown to modu-
late glutamatergic transmission through a reduction
without blockade [51]. NMDA antagonism was felt
to be effective in eliminating hyperalgesia associated
with migraine [52], as well a “secondary hyperalge-
sia” with exaggerated responses to noxious stimuli in
areas adjacent to the pain. NMDA blockade was rec-
ommended to treat chronic daily headache [53]. This
group also addressed how a genetic predisposition
(“third hyperalgesia”) may lead to a “chronicization”
of migraine through NMDA stimulation [54].
THC and CBD phytocannabinoids also act as
neuroprotective antioxidants against glutamate
neurotoxicity and cell death mediated via NMDA,
AMPA and kainate receptors [55], independently of
cannabinoid receptors, and exceed the antioxidant
potency of vitamins C and E.
Migraine is a complex neurochemical disorder with
myriad effects beyond pain. Its tendency to produce
photophobia and phonophobia, even between discreet
attacks [56], may be considered suggestive of a “sen-
sory hyperalgesia,” as these normally tolerated sensa-
tions take on painful proportions.
The combination of endocannabinoids and their
inactive precursors have been dubbed an entourage
effect [57], and an analogous synergy of phytocan-
nabinoids, cannabis terpenoids and avonoids has also
been suggested and analyzed at some length [58]. The
unique attributes of cannabis to affect serotonergic,
dopaminergic, opioid, anti-inammatory, and NMDA
mechanisms of migraine, both acutely and prophylac-
tically, have rendered it a proposed “ideal drug” for its
treatment [5].
Migraine is a strongly genetic disorder, but similar
symptoms are acquired under conditions of closed
head injury, where the “post-traumatic syndrome
displays similar symptoms. A protective role of
endocannabinoids in such settings is evident in the
ndings that 2-AG is elevated after experimental brain
injury, and that it plays an important neuroprotective
role [59].
Unfortunately, no organized clinical trials of can-
nabis in migraine have been performed. While docu-
mentation of the use of cannabis for migraine suggests
a 4000 year history, and it was a major indication for
cannabis medicines in Western society between 1842
and 1942 [5], there have been few modern studies be-
yond the “anecdotal” [5; 60–62]. Surveys in California
indicate that of 2480 patients served by the Oakland
Cannabis Buyers’ Club, 127, or 5%, sought cannabis
for treatment of chronic migraines [63]. Success rates
of some 80% with North American strains of canna-
bis have been estimated based on clinical contact [5].
Experience in prophylactic use of Marinol® (synthetic
THC) in some ten patients was disappointing, with
some decrement in frequency and severity of attacks,
but not total remission or “cures” claimed by 19
th
century authors with extracts of Indian hemp [5]. The
difference may well be due to a nearly total dearth of
cannabidiol in North American cannabis strains [64]
(see discussion below), and the observed possibility of
CBD modulation of serotonergic function [17]. More
formal documentation of clinical efcacy would be dis-
tinctly welcome.
Clinical Endocannabinoid Deciency (CECD)
34
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
35
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
Fibromyalgia
Fibromyalgia, or myofascial pain syndrome, is
an extremely common but controversial condition,
whose very basis has been questioned, particularly
among neurologists [65]. Even this author must ad-
mit to past prejudice in labeling it a “semi-mythical
pseudo-disease.” Notwithstanding these opinions, the
condition is the most frequent diagnosis in American
rheumatology practices. Bennett has provided an
excellent review [66], emphasizing new insights into
bromyalgia as a condition indicative of “central sen-
sitization” and amplication of somatic nociception.
While no clear chemical or anatomical pathology has
been claried in tender muscle points, these present
a self-sustaining and amplifying inuence on pain
perception in the brain over time, and lead to a con-
comitant disturbances in restful sleep, manifestations
of dysautonomia, and prevalent secondary depression.
Interestingly, the application of standard antidepres-
sant medication to the latter, and pharmacotherapy in
general, provide disappointing results in bromyalgia
treatment. Has a promising therapeutic avenue been
missed?
Returning to the work of Nicolodi and Sicuteri, the
“secondary hyperalgesia” manifested by an increased
response to noxious stimuli in areas adjacent to the
pain is common to migraine and bromyalgia (see be-
low). These authors suggested NMDA blockade as an
approach to pain in defects of serotonergic analgesia in
bromyalgia [67].
Several studies of Richardson and her group pro-
vide key support for a relation of bromyalgia and
similar conditions to a clinical endocannanabinoid
deciency. An initial study [68] demonstrated that
intrathecal injection of SR141716A, a powerful
cannabinoid antagonist/inverse agonist, resulted in
thermal hyperalgesia in mice. This suggests that
the endocannabinoid system regulates nociceptive
thresholds, and that absence of such regulation, or
endocannabinoid hypofunction, underlies hyperal-
gesia and related chronic pain conditions. In a sub-
sequent study [69], oligonucleotides directed against
CB
1
mRNA produced signicant hyperalgesia. Ad-
ditionally, the hyperalgesic effect of SR141716A was
blocked in a dose-dependent manner by co-adminis-
tration of two NMDA receptor antagonists, again sup-
porting tonic activity of the endocannabinoid system
under normal conditions. On this basis, it was sug-
gested that cannabinoid agonists would be applicable
to treatment of chronic pain conditions unresponsive
to opioid analgesics.
Further investigation demonstrated that intrathe-
cal AEA totally blocked carrageenan-induced spinal
thermal hyperalgesia, while having no effect on nor-
mal thermal sensory and antinociceptive thresholds
[70]. Additionally, AEA inhibited K
+
and capsaicin-
evoked calcitonin gene-related peptide (CGRP) re-
lease, and CB
1
receptors were identied in rat sensory
neurons and trigeminal ganglion. On this basis, the
authors recommended cannabinoids for disorders
driven by a primary afferent barrage (e.g., allodynia,
visceral hyperalgesia, temporomandibular joint pain
(TMJ), and reex sympathetic dystrophy (RSD)), and
that such treatment could be effective a sub-psychoac-
tive dosages.
Another study examined peripheral mechanisms
[71], wherein AEA acted on CB
1
to reduce hyperal-
gesia and inammation via inhibition of CGRP neu-
rosecretion in capsaicin activated nerve terminals.
This is akin to mechanisms of “sterile inammation”
observed centrally in migraine, where CGRP is felt
to be an important mediator [5]. Overall the results
supported the notion that endocannabinoids modu-
late neurogenic inammation through inhibition of
peripheral terminal neurosecretion in capsaicin-sen-
sitive bers. AEA demonstrated anti-edema effects
in addition to anti-hyperalgesia. Similar implications
were provided by another study [72], in which WIN
55,212–2, a powerful CB
1
agonist, blocked capsaicin-
induced hyperalgesia in rat paws. Once more, the ben-
et occurred at a dosage that did not produce analgesia
or motor impairment, suggesting therapeutic benet
of cannabinoids without adverse effects. Similarly, lo-
cal THC administration was evaluated in capsaicin-in-
duced pain in rhesus monkeys [73], where, once more,
pain was effectively reduced at low dosage, and was
blocked by a CB
1
antagonist.
Another concept that is important to understand-
ing of bromyalgia is “wind-up,” a central sensitiza-
tion of posterior horn neurons in pain pathways that
occurs secondarily to tonic impulses form nociceptive
afferent C bers dependent on NMDA and substance
P synaptic mechanisms in the spinal cord [74]. Simi-
lar mechanisms were implicated in TMJ dysfunction
and RSD/CRP syndromes. The authors felt that some
unknown peripheral tonic mechanism maintains
allodynia, hyperalgesia, central sensitization and en-
hanced wind-up. Unfortunately, an obvious explana-
tion was overlooked. In a previous publication [75],
it was demonstrated that of wind-up was decreased in
dose-dependent fashion by WIN 55,212 in spinal wide
dynamic range and nociceptive-specic neurons. Thus,
cannabinoids were able to suppress facilitation of spi-
nal responses after repetitive noxious stimuli without
impairment of non-nociceptive functions.
On a practical level, once more there have been no
formal clinical trials of cannabis or THC in treatment
of bromyalgia. However, 21 California patients listed
bromyalgia and 11 myofascial pain (1.3% of a clini-
cal population of 2480 subjects) as primary diagnoses
leading to their usage of clinical cannabis [63]. Anec-
dotal reports to this author and other clinicians sup-
port unique efcacy of cannabis beyond conventional
pharmacotherapy for alleviation of pain, dysphoria
and sleep disturbances.
Irritable Bowel Syndrome (IBS)
IBS is another difcult clinical syndrome for pa-
tients and their physicians. It is characterized by
uctuating symptoms of gastrointestinal pain, spasm,
distention, and varying degrees of constipation or es-
pecially diarrhea. These may be triggered by infection,
Ethan B. Russo
34
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
35
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
but dietary indiscretions also gure prominently in
discrete attacks. Although many clinicians regard it as
a “diagnostic wastebasket,irritable bowel syndrome
represents the most frequent referral diagnosis for
American gastroenterologists. Once more, a wide va-
riety of treatments including atropinic agents, antide-
pressants and others affecting a myriad of neurotrans-
mitter systems are prescribed, often with inadequate
clinical benets.
That endocannabinoids are important in GI func-
tion was powerfully underlined by the fact that 2-
arachidonylglycerol (2-AG) was rst isolated in canine
gut [76].
In a recent review [77], the concept of “functional”
bowel disorders as disturbances displaying “visceral
hypersensitivity” was emphasized, involving a veri-
table symphony of neuroactive and pro-inammatory
modulators. In the susceptible subject, these lead to
gastrointestinal allodynia and hyperalgesia to stimuli
that would not discomt the unaffected individual.
The role of vanilloid mechanisms in IBS was also ex-
plored, and it is worth emphasizing that anandamide
is an endogenous agonist at VR
1
receptors, as is the
phytocannabinoid cannabidiol (CBD) [78]. Repetitive
VR
1
stimulation rapidly produces a sensory neuron
refractory state that would be a clinical advantage in
treatment of visceral hypersensitivity.
Pertwee has examined the relationship of cannabi-
noids to gastrointestinal function in depth [79]. To
summarize: The enteric nervous systems of mammals
express CB
1
and stimulation depresses gastrointesti-
nal motility, especially through inhibition of contrac-
tile neurotransmitter release. Observed effects include
delayed gastric emptying, some decrease in peptic acid
production, and slowed enteric motility, inhibition
of stimulated acetylcholine release, peristalsis, and
both cholinergic and non-adrenergic non-cholinergic
(NANC) contractions of smooth muscle, whether cir-
cular or longitudinal. These effects are mediated at the
brain level as well as in the GI tract (This supports a
chestnut frequently invoked by this author, ‘The brain
and the gut speak the same language.”). These effects
are opposed by CB
1
antagonists (e.g., SR141716A).
This would strongly support the notion that GI motil-
ity is under tonic control of the endocannabinoid sys-
tem. The latter concept was reinforced by additional
investigation from the same laboratory [80], in which
it was demonstrated that the virtually all of the immu-
noreactive myenteric neurons in the ganglia of rat and
guinea pig expressed CB
1
receptors, and that there was
a close correlation of such receptors to bers labeled
for synaptic protein, suggesting a fundamental role
in neurotransmitter release. Additionally, it has been
shown that chronic intestinal inammation results in
an up-regulation or sensitization of cannabinoid recep-
tors [81]. CBD has little effect on intestinal motility on
its own, but synergizes the effect of THC in slowing
transit of a charcoal meal when used in concert [82].
In the basis of available data, Di Carlo and Izzo
recommended the application of cannabinoid drugs
in treatment of IBS in humans [83]. To date, those
studies have not eventuated, but cannabis has a long
history in treating cholera, intestinal colic and related
disorders (reviewed in [84]), and cannabis gures
prominently in IBS treatment in testimonials on the
Internet. Though anecdotal, reports suggest unique
efcacy of symptomatic relief at cannabis dosages that
do not impair activities of daily living. In comparison,
recent trends in pharmacotherapy provide interest-
ing contrasts. Alosetron, a 5-HT
3
receptor antagonist
marketed for females with diarrhea-predominant IBS
produces only a 12–17% therapeutic gain [85], and
was temporarily removed from the American market
due to fatal cases of ischemic colitis with attendant
obstipation. Tegaserod, a 5-HT
4
receptor agonist
marketed to women with constipation-predominant
IBS, is reportedly well tolerated, but provides only a
5–15% improvement over placebo [85]. This “push-
pull” dichotomy of serotonergic function in IBS is
strongly suggestive that such efforts are barking up
the wrong neurotransmitter tree. Rational analysis
suggests that endocannabinoids may well be the more
likely therapeutic neuromodulatory target, and that
phytocannabinoid treatment might represent a more
efcacious and safer therapeutic approach. In particu-
larly severe IBS cases, the employment of a foaming
rectal preparation of a whole cannabis extract might
be considered.
Comorbidities of Migraine, Fibromyalgia
and Irritable Bowel Syndrome
Further examination of pertinent literature sup-
ports that there are very interesting relationships
between migraine, bromyalgia and IBS. Recently,
a syndrome of cutaneous allodynia associated with
migraine has been reported [86], and experimen-
tally, repetitive noxious stimulation of the skin in
migraineurs between attacks facilitates pain percep-
tion [87]. Nicolodi, Sicuteri et al. similarly noted a
decreased pain threshold in migraineurs tested with
over-distension of upper extremity veins, but not mere
pressure from a sphygmomanometer cuff [88], merit-
ing a label for migraine as a “visceral systemic sensory
disorder.” The same team noted a baseline fragility
of serotonergic systems in migraine and bromyalgia
[89], plus the co-occurrence of primary headache in
97% of 201 bromyalgia patients. In a later study
[67], they supported the concept that both disorders
represented a failure of serotonergic analgesia and
NMDA-mediated neuronal plasticity. Other observa-
tions included the induction of bromyalgic symptoms
by the drug fenclonine in migraineurs but not others,
and the production of migraine de novo in bromyalgia
patients without prior history after administration
of nitroglycerine 0.6 mg sublingually. Similarly, an
American group [90] examined 101 patients with the
transformed migraine form of chronic daily headache,
and were able to diagnose 35.6% as having comorbid
bromyalgia. Similarly, a high lifetime prevalence of
migraine, IBS, depression and panic disorder were
observed in 33 women meeting American College of
Rheumatology criteria of bromyalgia [91].
Clinical Endocannabinoid Deciency (CECD)
36
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
37
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
Sperber et al. examined separate groups of IBS and
bromyalgia patients [92]. Of the IBS cohort, 31.6%
had bromyalgia with signicant numbers of tender
muscle points compared to controls. Similarly, 32% of
bromyalgia patients met diagnostic criteria of IBS. In
addition to these correlations, Bennett added irritable
bladder syndrome to the comorbidities of bromyalgia
[66], supporting a concomitant visceral hyperalgesia
[93; 94] in a condition where cannabis extracts have
already proven efcacious [95].
Most recently, in an experimental protocol, it was
demonstrated that IBS patients displayed cutaneous
hyperalgesia that was suppressed by temporary rectal
anesthesia with lidocaine [96], indicating central sen-
sitization.
Broadening the Concept of Clinical
Endocannabinoid Deciency
One may quickly see that certain patients display
symptoms of all three disorders, or additional ones
considered “functional. With accrual of sufcient
numbers of complaints lacking objective medical sup-
port, one assigns the label of somatization disorder.
Given the above data, however, one might reasonably
ask three questions in such contexts: 1) Are there as
yet unelucidated biochemical explanations for these
disorders? 2) Might endocannabinoid deciency ex-
plain their pathophysiology? 3) Are the symptoms al-
leviated by clinical cannabis?
Globus hystericus and similar symptoms are
frequently relegated to the psychogenic realm, but
as a spasmodic disorder, it may well represent an
endocannabinoid deciency (CECD), as muscle tone
(and tremor associated with demyelination) have been
demonstrated to be under tonic endocannabinoid con-
trol in experimental animals [97]. Cannabis extracts
have already proven efcacious in treatment of spas-
ticity [98; 99].
Similarly, premature ejaculation in men is conven-
tionally perceived as “psychological.” This seems less
tenable, when anecdotes support that cannabis pro-
longs latency, and proof is apparent in the dose respon-
sive delay in ejaculation in rats noted in experiments
with HU 210, a powerful CB
1
agonist [100].
A more obvious set of correlating conditions would
be those of causalgia, allodynia and phantom limb
pain, where application of cannabis based medicine
extracts has already proven medically effective [99;
101]. Perhaps it will be demonstrable in the future
that such conditions are associated with focal or spinal
CECD states.
It has long been known that cannabinoids lower
intraocular pressure in glaucoma (reviewed [102]),
but only recently noted that that the mechanism is
under tonic endocannabinoid control. Glaucoma also
represents a vascular retinopathy for which cannabis
may be neuroprotective. Perhaps an endocannabinoid
deciency is operative here as well.
Cannabis has had numerous historical applications
to obstetrics and gynecology (reviewed [103]). This
suggests usage of cannabinoid treatment in spasmodic
dysmenorrhea, hyperemesis gravidarum, and regula-
tion of the uterine milieu in fertilization and unex-
plained fetal wastage, where endocannabinoid mecha-
nisms have been demonstrated or implicated. Further
investigation may shed light on whether dysregulation
of the system underlies their pathophysiology.
In the pediatric realm, the entity of infantile colic
has remained enigmatic. This disturbing anomaly is as-
sociated with apparent visceral sensitivity and distinct
dysphoria, and is frequently medically recalcitrant to
even desperate treatment measures with medications
with serious adverse effect proles. This author posits
this to be another developmental endocannabinoid
deciency state that is likely amenable to phytocan-
nabinoid treatment.
Endocannabinoid mechanisms also regulate
bronchial function [104], and therapeutic efcacy in
asthma treatment with cannabis preparations has
been long known [105]. Based on similar analyses of
the multi-organ involvement of cystic brosis [106],
Fride has proposed endocannabinoid deciencies as
underlying the pathophysiology of that disorder, and
its treatment with phytocannabinoids.
In the psychiatric realm, bipolar disorder has been
therapeutically recalcitrant to high dose antidepres-
sants, but anecdotal data support cannabis efcacy
[107]. Whether endocannabinoid tone is too low in
the disorder would be conjectural at this time, but in
the instance of post-traumatic stress disorder (PTSD),
such a foundation seems likely, as endocannabinoids
have been demonstrated as essential to the extinction
of aversive memories in experimental animals [108].
Recent work by Wallace et al. has also demon-
strated that convulsive thresholds are also under
endocannabinoid control [109; 110], and that THC
prevents 100% of subsequent seizures, far in excess
of the capabilities of phenobarbital and phenytoin.
Affected rats demonstrated both acute increases in
endocannabinoid production and a long-term up-regu-
lation of CB
1
production as apparent compensatory ef-
fects counteracting glutamate excitotoxicity. Based on
this, one might conjecture that similar changes accrue
when seizures are employed therapeutically as electro-
convulsive therapy (ECT), in treatment of intractable
depression. It seems that the resultant memory loss
and prolonged improvement in mood may well be at-
tributable to an increase in endocannabinoid levels
rectifying their previous inadequacy.
Recent theory on depression suggests that mere
deciencies of serotonin and norepinephrine may be
insufcient explanations of the disorder, but rather,
innate neuroplasticity is inherently impaired and
requires specic treatment [111]. Cannabinoids
certainly seem to enhance that plasticity with their
neuroprotective abilities [112; 113], and should be fur-
ther explored therapeutically.
The apoptotic and anti-angiogenic properties of
endo- and phytocannabinoids in various cancers (re-
viewed [114; 115]) raise the hypothesis that certain
people who are especially susceptible to malignancy
may be endocannabinoid decient.
Ethan B. Russo
36
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
37
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
Conclusions
Clinical Endocannabinoid Deciency:
Is It a Provable Concept?
The preceding material has pertained to conjectural
and experimental evidence of a conceptual alternative
biochemical explanation for certain disease manifes-
tations, but one must ask how these would obtain?
Baker et al. have described how endocannabinoids
may demonstrate an impairment threshold if too high,
and a range of normal function below which a decit
threshold may be crossed [112]. Syndromes of CECD
may be congenital or acquired. In the former case, one
could posit that genetically-susceptible individuals
might produce inadequate endocannabinoids, or that
their degradation is too rapid. The same conditions
might be acquired in injury or infection. Unfortu-
nately, the regulation of endocannabinoid synthesis
and degradation are far from fully elucidated (re-
viewed [116]). While a single enzyme, anandamide
synthase, catalyzes AEA production, its degrada-
tion by fatty acid amidohydrolase (FAAH), is shared
with many substrates. To complicate matters, an
endocannabinoid with antagonistic properties at CB
1
called virodhamine (virodha, Sanskrit for “opposi-
tion”) has recently been discovered [117]. Further re-
search may shed light on these relationships.
In the meantime, a clinical agent that modies
endocannabinoid function will soon be clinically avail-
able in the form of cannabidiol. Recent research has
demonstrated that although THC does not share VR
1
agonistic activity with AEA, CBD does so to a similar
degree as capsaicin [78]. What is more, CBD inhibits
uptake of the endocannabinoid anandamide (AEA),
and weakly inhibits its hydrolysis. The presence of
this component in available cannabis based medicine
extracts portends to vastly extend the clinical appli-
cations and therapeutic efcacy of this re-emerging
modality [118–120].
It is highly likely that additional regulatory roles
for endocannabinoids will be discovered for this neuro-
and immunomodulatory system. Some simple human
experiments may be valuable, such as cerebrospinal
uid assay of AEA and 2-AG before and after ECT
treatment. It is likely in the future that positron emis-
sion tomography (PET) or functional magnetic reso-
nance imaging (fMRI) for cannabinoid ligands may
clarify these concepts.
This article has examined the inter-relationships
of three clinical syndromes and biochemical basis in
endocannabinoid function, as well as reecting on
other conditions that may display similar correlations.
Only time and the scientic method will ascertain
whether a new paradigm is applicable to human physi-
ology and treatment of its derangements. Our insight
into these possibilities is dependent on the contribu-
tion of one unique healing plant; for clinical cannabis
has become a therapeutic compass to what modern
medicine fails to cure.
REFERENCES
1 Freud S. Project for a scientic psychology. Trans. Strachey J.
In: The standard edition of the complete psychological works of
Sigmund Freud. Vol. 1, 24 vols. London: Hogarth Press.; 1966. p.
281–343.
2 Di Marzo V. Endocannabinoids’ and other fatty acid derivatives with
cannabimimetic properties: biochemistry and possible physiopath-
ological relevance. Biochim Biophys Acta 1998; 1392:153–175.
3 Russo EB. Role of cannabis and cannabinoids in pain management.
In: Weiner RS, editors. Pain management: A practical guide for
clinicians. 6th edit., 2 vols. Boca Raton, FL: CRC Press; 2002. p.
357–375.
4 Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol 2001;
63:569–611.
5 Russo EB. Hemp for headache: An in-depth historical and scientic
review of cannabis in migraine treatment. Journal of Cannabis
Therapeutics 2001; 1:21–92.
6 Russo EB. Handbook of psychotropic herbs: A scientic analysis of
herbal remedies for psychiatric conditions. 2001. Haworth Press,
Binghamton, NY.
7 Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Grifn
G, et al. Isolation and structure of a brain constituent that binds to
the cannabinoid receptor. Science 1992; 258:1946–1949.
8 Herkenham MA. Localization of cannabinoid receptors in brain:
relationship to motor and reward systems. In: Korman SG, Barchas
JD, editors. Biological Basis of Substance Abuse. London: Oxford
University; 1993. p. 187–200.
9 Fride E, Mechoulam R. Pharmacological activity of the cannabinoid
receptor agonist, anandamide, a brain constituent. Eur J Pharmacol
1993; 231:313–314.
10 Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of
migraine headache in the United States. Relation to age, income,
race, and other sociodemographic factors. Journal of the American
Medical Association 1992; 267:64–69.
11 Lipton RB, Stewart WF. Migraine in the United States: A review of
epidemiology and health care use. Neurology 1993; 43:S6–10.
12 Russo E. Cannabis for migraine treatment: The once and future pre-
scription? An historical and scientic review. Pain 1998; 76:3–8.
13 Volfe Z, Dvilansky A, Nathan I. Cannabinoids block release of sero-
tonin from platelets induced by plasma from migraine patients. Int
J Clin Pharmacol Res 1985; 5:243–246.
14 Spadone C. Neurophysiologie du cannabis [Neurophysiology of can-
nabis]. Encephale 1991; 17:17–22.
15 Fan P. Cannabinoid agonists inhibit the activation of 5-HT3 recep-
tors in rat nodose ganglion. Journal of Neurophysiology 1995; 73:
907–910.
16 Boger DL, Patterson JE, Jin Q. Structural requirements for 5-HT2A
and 5-HT1A serotonin receptor potentiation by the biologically ac-
tive lipid oleamide. Proc Natl Acad Sci U S A 1998; 95:4102–4107.
17 Hall B, Burnett A, Christians A, Halley C, Parker LA, Russo E, et al.
(2004). Pharmacology of cannabidiol at serotonin receptors. West-
ern Pharmacology Society, Honolulu, HI.
18 Russo EB, Macarah CM, Todd CL, Medora R, Parker K. (2000). Phar-
macology of the essential oil of hemp at 5HT1A and 5HT2a recep-
tors. 41st Annual Meeting of the American Society of Pharmacog-
nosy, Seattle, WA.
19 Kimura T, Ohta T, Watanabe K, Yoshimura H, Yamamoto I. Anan-
damide, an endogenous cannabinoid receptor ligand, also interacts
with 5-hydroxytryptamine (5-HT) receptor. Biol Pharm Bull 1998;
21:224–226.
20 Peroutka SJ. The pharmacology of current anti-migraine drugs.
Headache 1990; 30:5–11; discussion 24–18.
21 Peroutka SJ. Dopamine and migraine. Neurology 1997; 49:650–
656.
22 Ferri S, Cavicchini E, Romualdi P, Speroni E, Murari G. Possible medi-
ation of catecholaminergic pathways in the antinociceptive effect
of an extract of Cannabis sativa L. Psychopharmacology 1986; 89:
244–247.
23 Stefano GB, Salzet B, Rialas CM, Pope M, Kustka A, Neenan K, et al.
Morphine- and anandamide-stimulated nitric oxide production in-
hibits presynaptic dopamine release. Brain Res 1997; 763:63–68.
24 Muller-Vahl KR, Schneider U, Prevedel H, Theloe K, Kolbe H, Dal-
drup T, et al. Delta9-Tetrahydrocannabinol (THC) is Effective in the
Treatment of Tics in Tourette Syndrome: a 6-Week Randomized Trial.
J Clin Psychiatry 2003; 64:459–465.
Clinical Endocannabinoid Deciency (CECD)
38
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
39
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
25 Müller-Vahl KR, Schneider U, Kolbe H, Emrich HM. Treatment of
Tourette’s syndrome with delta-9-tetrahydrocannabinol. Am J Psy-
chiatry 1999; 156:495.
26 Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D. Elevated
endogenous cannabinoids in schizophrenia. Neuroreport 1999; 10:
1665-1669.
27 Burstein S. Eicosanoids as mediators of cannabinoid action. In:
Murphy L, Bartke A, editors. Marijuana/Cannabinoids: Neurobiology
and neurophysiology of drug abuse. Boca Raton: CRC Press; 1992.
p. 73–91.
28 Evans AT, Formukong EA, Evans FJ. Actions of cannabis constituents
on enzymes of arachidonate metabolism: anti-inammatory poten-
tial. Biochem Pharmacol 1987; 36:2035–2037.
29 Formukong EA, Evans AT, Evans FJ. Analgesic and antiinammatory
activity of constituents of Cannabis sativa L. Inammation 1988;
12:361–371.
30 Formukong EA, Evans AT, Evans FJ. The inhibitory effects of
cannabinoids, the active constituents of Cannabis sativa L. on hu-
man and rabbit platelet aggregation. J Pharm Pharmacol 1989; 41:
705–709.
31 McPartland J. Cannabis and eicosanoids: A review of molecular
pharmacology. Journal of Cannabis Therapeutics 2001; 1:71–83.
32 Burstein S, Levin E, Varanelli C. Prostaglandins and cannabis. II.
Inhibition of biosynthesis by the naturally occurring cannabinoids.
Biochem Pharmacol 1973; 22:2905–2910.
33 Schaefer CF, Brackett DJ, Gunn CG, Dubowski KM. Decreased platelet
aggregation following marihuana smoking in man. J Okla State Med
Assoc 1979; 72:435–436.
34 Evans FJ. Cannabinoids: The separation of central from peripheral
effects on a structural basis. Planta Med 1991; 57:S60–67.
35 Hampson AJ, Hill WA, Zan-Phillips M, Makriyannis A, Leung E, Eglen
RM, et al. Anandamide hydroxylation by brain lipoxygenase:metab-
olite structures and potencies at the cannabinoid receptor. Biochim
Biophys Acta 1995; 1259:173–179.
36 Fimiani C, Liberty T, Aquirre AJ, Amin I, Ali N, Stefano GB. Opiate,
cannabinoid, and eicosanoid signaling converges on common intra-
cellular pathways nitric oxide coupling. Prostaglandins Other Lipid
Mediat 1999; 57:23–34.
37 Fettes I, Gawel M, Kuzniak S, Edmeads J. Endorphin levels in head-
ache syndromes. Headache 1985; 25:37–39.
38 Wiegant VM, Sweep CG, Nir I. Effect of acute administration of delta
1-tetrahydrocannabinol on beta- endorphin levels in plasma and
brain tissue of the rat. Experientia 1987; 43:413–415.
39 Mailleux P, Vanderhaeghen JJ. Delta-9-tetrahydrocannabinol regu-
lates substance P and enkephalin mRNAs levels in the caudate-pu-
tamen. Eur J Pharmacol 1994; 267:R1–3.
40 Meng ID, Manning BH, Martin WJ, Fields HL. An analgesia circuit
activated by cannabinoids. Nature 1998; 395:381–383.
41 Goadsby PJ, Gundlach AL. Localization of 3H-dihydroergotamine-
binding sites in the cat central nervous system: relevance to mi-
graine. Ann Neurol 1991; 29:91–94.
42 Lichtman AH, Martin BR. Spinal and supraspinal components of
cannabinoid-induced antinociception. J Pharmacol Exp Ther 1991;
258:517–523.
43 Behbehani MM. Functional characteristics of the midbrain periaq-
ueductal gray. Prog Neurobiol 1995; 46:575–605.
44 Castro ME, Pascual J, Romon T, del Arco C, del Olmo E, Pazos A. Dif-
ferential distribution of [3H]sumatriptan binding sites (5-HT1B,
5- HT1D and 5-HT1F receptors) in human brain: focus on brainstem
and spinal cord. Neuropharmacology 1997; 36:535–542.
45 Manzanares J, Corchero J, Romero J, Fernandez-Ruiz JJ, Ramos JA,
Fuentes JA. Chronic administration of cannabinoids regulates pro-
enkephalin mRNA levels in selected regions of the rat brain. Brain
Res Mol Brain Res 1998; 55:126–132.
46 Walker JM, Huang SM, Strangman NM, Tsou K, Sanudo-Pena MC. Pain
modulation by the release of the endogenous cannabinoid anan-
damide. Proceedings of the National Academy of Sciences 1999; 96:
12198–12203.
47 Hamann W, di Vadi PP. Analgesic effect of the cannabinoid analogue
nabilone is not mediated by opioid receptors. Lancet 1999; 353:
560.
48 Nicolodi M. Painful and non-painful effects of low doses of mor-
phine in migraine sufferers partly depend on excitatory amino acids
and gamma- aminobutyric acid. Int J Clin Pharmacol Res 1998; 18:
79–85.
49 Storer RJ, Goadsby PJ. Trigeminovascular nociceptive transmission
involves N-methyl-D-aspartate and non-N-methyl-D-aspartate glu-
tamate receptors. Neuroscience 1999; 90:1371–1376.
50 Shen M, Piser TM, Seybold VS, Thayer SA. Cannabinoid receptor
agonists inhibit glutamatergic synaptic transmission in rat hippo-
campal cultures. J Neurosci 1996; 16:4322–4334.
51 Shen M, Thayer SA. Delta-9-tetrahydrocannabinol acts as a partial
agonist to modulate glutamatergic synaptic transmission between
rat hippocampal neurons in culture. Mol Pharmacol 1999; 55:8–13.
52 Nicolodi M, Sicuteri F. Exploration of NMDA receptors in migraine:
Therapeutic and theoretic implications. Int J Clin Pharmacol Res
1995; 15:181–189.
53 Nicolodi M, Del Bianco PL, Sicuteri F. Modulation of excitatory
amino acids pathway: a possible therapeutic approach to chronic
daily headache associated with analgesic drugs abuse. Int J Clin
Pharmacol Res 1997; 17:97–100.
54 Nicolodi M, Sicuteri F. Negative modultors [sic] of excitatory amino
acids in episodic and chronic migraine: preventing and reverting
chronic migraine. Special lecture 7th INWIN Congress. Int J Clin
Pharmacol Res 1998; 18:93–100.
55 Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and
(-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants.
Proc Natl Acad Sci U S A 1998; 95:8268–8273.
56 Main A, Dowson A, Gross M. Photophobia and phonophobia in mi-
graineurs between attacks. Headache 1997; 37:492–495.
57 Mechoulam R, Ben-Shabat S. From gan-zi-gun-nu to anandamide
and 2-arachidonoylglycerol: The ongoing story of cannabis. Nat
Prod Rep 1999; 16:131–143.
58 McPartland JM, Russo EB. Cannabis and cannabis extracts: Greater
than the sum of their parts? Journal of Cannabis Therapeutics 2001;
1:103–132.
59 Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer
A, Mechoulam R, et al. An endogenous cannabinoid (2-AG) is
neuroprotective after brain injury. Nature 2001; 413:527–531.
60 Mikuriya TH. 1997. Chronic migraine headache: Five cases success-
fully treated with marinol and/or illiciit cannabis.
61 Grinspoon L, Bakalar JB. Marihuana, the forbidden medicine. 1993.
Yale University Press, New Haven.
62 el-Mallakh RS. Marijuana and migraine. Headache 1987; 27:442–
443.
63 Gieringer D. Medical use of cannabis: Experience in California. In:
Grotenhermen F, Russo E, editors. Cannabis and cannabinoids:
Pharmacology, toxicology, and therapeutic potential. Binghamton,
NY: Haworth Press; 2001. p. 153–170.
64 Gieringer D. Medical cannabis potency testing project. Bulletin of
the Multidisciplinary Association for Psychedelic Studies 1999; 9:
20–22.
65 Bohr T. Problems with myofascial pain syndrome and bromyalgia
syndrome. Neurology 1996; 46:593–597.
66 Bennett RM. Rational management of bromyalgia. Rheum Dis Clin
North Am 2002; 28:xiii–xv.
67 Nicolodi M, Volpe AR, Sicuteri F. Fibromyalgia and headache. Failure
of serotonergic analgesia and N-methyl-D-aspartate-mediated neu-
ronal plasticity: Their common clues. Cephalalgia 1998; 18 (Suppl
21):41–44.
68 Richardson JD, Aanonsen L, Hargreaves KM. SR 141716A, a
cannabinoid receptor antagonist, produces hyperalgesia in un-
treated mice. Eur J Pharmacol 1997; 319:R3–4.
69 Richardson JD, Aanonsen L, Hargreaves KM. Hypoactivity of the spi-
nal cannabinoid system results in NMDA-dependent hyperalgesia. J
Neurosci 1998; 18:451–457.
70 Richardson JD, Aanonsen L, Hargreaves KM. Antihyperalgesic ef-
fects of spinal cannabinoids. Eur J Pharmacol 1998; 345:145–153.
71 Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyper-
algesia and inammation via interaction with peripheral CB1 recep-
tors. Pain 1998; 75:111–119.
72 Li J, Daughters RS, Bullis C, Bengiamin R, Stucky MW, Brennan J, et
al. The cannabinoid receptor agonist WIN 55,212-2 mesylate blocks
the development of hyperalgesia produced by capsaicin in rats. Pain
1999; 81:25–33.
73 Ko MC, Woods JH. Local administration of delta9-tetrahydrocannab-
inol attenuates capsaicin-induced thermal nociception in rhesus
monkeys: a peripheral cannabinoid action. Psychopharmacology
(Berl) 1999; 143:322–326.
74 Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal
sensitization and temporal summation of second pain (wind-up) in
patients with bromyalgia syndrome. Pain 2001; 91:165–175.
75 Strangman NM, Walker JM. Cannabinoid WIN 55,212–2 inhibits the
activity-dependent facilitation of spinal nociceptive responses. J
Ethan B. Russo
38
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
39
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
Neurophysiol 1999; 82:472–477.
76 Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE,
Schatz AR, et al. Identication of an endogenous 2-monoglyceride,
present in canine gut, that binds to cannabinoid receptors. Bio-
chem Pharmacol 1995; 50:83–90.
77 Holzer P. Gastrointestinal afferents as targets of novel drugs for
the treatment of functional bowel disorders and visceral pain. Eur J
Pharmacol 2001; 429:177–193.
78 Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi
I, et al. Molecular targets for cannabidiol and its synthetic ana-
logues: effect on vanilloid VR1 receptors and on the cellular uptake
and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001;
134:845–852.
79 Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut 2001;
48:859–867.
80 Coutts AA, Irving AJ, Mackie K, Pertwee RG, Anavi-Goffer S. Lo-
calisation of cannabinoid CB(1) receptor immunoreactivity in the
guinea pig and rat myenteric plexus. J Comp Neurol 2002; 448:
410–422.
81 Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto L, Iuvone T, et al.
Cannabinoid CB1-receptor mediated regulation of gastrointestinal
motility in mice in a model of intestinal inammation. Br J Pharma-
col 2001; 134:563–570.
82 Anderson PF, Jackson DM, Chesher GB. Interaction of delta-9-tetra-
hydrocannabinol and cannabidiol on intestinal motility in mice. J
Pharm Pharmacol 1974; 26:136–137.
83 Di Carlo G, Izzo AA. Cannabinoids for gastrointestinal diseases: po-
tential therapeutic applications. Expert Opin Investig Drugs 2003;
12:39–49.
84 Russo E. Cannabinoids in pain management. Study was bound to
conclude that cannabinoids had limited efcacy. Brit Med J 2001;
323:1249–1250; discussion 1250–1241.
85 Talley NJ. Evaluation of drug treatment in irritable bowel syndrome.
Br J Clin Pharmacol 2003; 56:362–369.
86 Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An as-
sociation between migraine and cutaneous allodynia. Ann Neurol
2000; 47:614–624.
87 Weissman-Fogel I, Sprecher E, Granovsky Y, Yarnitsky D. Repeated
noxious stimulation of the skin enhances cutaneous pain percep-
tion of migraine patients in-between attacks: clinical evidence
for continuous sub-threshold increase in membrane excitability of
central trigeminovascular neurons. Pain 2003; 104:693–700.
88 Nicolodi M, Sicuteri R, Coppola G, Greco E, Pietrini U, Sicuteri F.
Visceral pain threshold is deeply lowered far from the head in mi-
graine. Headache 1994; 34:12–19.
89 Nicolodi M, Sicuteri F. Fibromyalgia and migraine, two faces of the
same mechanism. In: Filippini GA, editors. Recent advances in
tryptophan research. New York: Plenum Press; 1996. p. 373–379.
90 Peres MF, Young WB, Kaup AO, Zukerman E, Silberstein SD.
Fibromyalgia is common in patients with transformed migraine.
Neurology 2001; 57:1326–1328.
91 Hudson JI, Goldenberg DL, Pope HG, Jr., Keck PE, Jr., Schlesinger L.
Comorbidity of bromyalgia with medical and psychiatric disorders.
Am J Med 1992; 92:363–367.
92 Sperber AD, Atzmon Y, Neumann L, Weisberg I, Shalit Y, Abu-
Shakrah M, et al. Fibromyalgia in the irritable bowel syndrome:
studies of prevalence and clinical implications. Am J Gastroenterol
1999; 94:3541–3546.
93 Jaggar SI, Hasnie FS, Sellaturay S, Rice AS. The anti-hyperalgesic
actions of the cannabinoid anandamide and the putative CB2
receptor agonist palmitoylethanolamide in visceral and somatic
inammatory pain. Pain 1998; 76:189–199.
94 Jaggar SI, Sellaturay S, Rice AS. The endogenous cannabinoid
anandamide, but not the CB2 ligand palmitoylethanolamide, pre-
vents the viscero-visceral hyper-reexia associated with inamma-
tion of the rat urinary bladder. Neurosci Lett 1998; 253:123–126.
95 Brady CM, DasGupta R, Wiseman OJ, Berkley KJ, Fowler CJ. (2001).
Congress of the International Association for Cannabis as Medicine,
Berlin, Germany.
96 Verne GN, Robinson ME, Vase L, Price DD. Reversal of visceral and
cutaneous hyperalgesia by local rectal anesthesia in irritable bowel
syndrome (IBS) patients. Pain 2003; 105:223–230.
97 Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, et
al. Cannabinoids control spasticity and tremor in a multiple sclero-
sis model. Nature 2000; 404:84–87.
98 Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, et al.
Cannabinoids for treatment of spasticity and other symptoms re-
lated to multiple sclerosis (CAMS study): multicentre randomised
placebo-controlled trial. Lancet 2003; 362:1517–1526.
99 Wade DT, Robson P, House H, Makela P, Aram J. A preliminary con-
trolled study to determine whether whole-plant cannabis extracts
can improve intractable neurogenic symptoms. Clinical Rehabilita-
tion 2003; 17:18–26.
100Ferrari F, Ottani A, Giuliani D. Inhibitory effects of the cannabinoid
agonist HU 210 on rat sexual behaviour. Physiol Behav 2000; 69:
547–554.
101 Notcutt W, Price M, Miller R, Newport S, Phillips C, Simmonds S,
et al. Initial experiences with medicinal extracts of cannabis for
chronic pain: results from 34 “N of 1” studies. Anaesthesia 2004;
59:440-452.
102 Jarvinen T, Pate D, Laine K. Cannabinoids in the treatment of
glaucoma. Pharmacol Ther 2002; 95:203.
103 Russo E. Cannabis treatments in obstetrics and gynecology: A his-
torical review. Journal of Cannabis Therapeutics 2002; 2:5–35.
104 Pertwee RG, Ross RA. Cannabinoid receptors and their ligands.
Prostaglandins Leukot Essent Fatty Acids 2002; 66:101–121.
105 Williams SJ, Hartley JP, Graham JD. Bronchodilator effect of
delta1-tetrahydrocannabinol administered by aerosol of asth-
matic patients. Thorax 1976; 31:720–723.
106 Fride E. Cannabinoids and cystic brosis: A novel approach. Jour-
nal of Cannabis Therapeutics 2002; 2:59–71.
107 Grinspoon L, Bakalar JB. The use of cannabis as a mood stabilizer
in bipolar disorder: anecdotal evidence and the need for clinical
research. J Psychoactive Drugs 1998; 30:171–177.
108 Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG,
et al. The endogenous cannabinoid system controls extinction of
aversive memories. Nature 2002; 418:530–534.
109 Wallace MJ, Martin BR, DeLorenzo RJ. Evidence for a physiological
role of endocannabinoids in the modulation of seizure threshold
and severity. Eur J Pharmacol 2002; 452:295–301.
110 Wallace MJ, Blair RE, Falenski KW, Martin BR, DeLorenzo RJ. The
endogenous cannabinoid system regulates seizure frequency and
duration in a model of temporal lobe epilepsy. J Pharmacol Exp
Ther 2003; 307:129–137.
111 Delgado P, Moreno F. Antidepressants and the brain. Int Clin Psy-
chopharmacol 1999; 14 Suppl 1:S9–16.
112 Baker D, Pryce G, Giovannoni G, Thompson AJ. The therapeutic
potential of cannabis. Lancet Neurology 2003; 2:291–298.
113 Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain
injury: therapeutic implications. Trends Mol Med 2002; 8:58–61.
114 Guzman M. Cannabinoids: potential anticancer agents. Nat Rev
Cancer 2003; 3:745–755.
115 Maccarrone M, Finazzi-Agro A. The endocannabinoid system,
anandamide and the regulation of mammalian cell apoptosis. Cell
Death Differ 2003; 10:946–955.
116 Hillard CJ, Jarrahian A. Cellular accumulation of anandamide:
consensus and controversy. Br J Pharmacol 2003; 140:802–808.
117 Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao J,
et al. Characterization of a novel endocannabinoid, virodhamine,
with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther
2002; 301:1020–1024.
118 Russo EB. Cannabis-From pariah to prescription. Journal of Can-
nabis Therapeutics 2003; 3(3):1–29.
119 Whittle BA, Guy GW, Robson P. Prospects for new cannabis-based
prescription medicines. Journal of Cannabis Therapeutics 2001; 1:
183–205.
120 Whittle BA, Guy GW, Robson P. Cannabis and cannabinoids as
medicines. 2003. Pharmaceutical Press, London.
Clinical Endocannabinoid Deciency (CECD)
... Then, the immune functions cannot be separated in vivo from the activity of the endocrine and nervous systems. The cytokine regulation of the neuroendocrine system would mainly consisting of the modulation of the activity of FAAH, which is responsible for the functional status of the endogenous cannabinoid system, since an exaggerated activation of FAAH allow an endogenous cannabinoid deficiency, which has been described in most severe clinical conditions, including the disseminated neoplasms and the cardiovascular disorders [37,44]. On the other hand, both cannabinoids and MLT can reduce brain and heart ischemic diseases, and prevent the onset of atherosclerosis [26,29]. ...
... The most clinically relevant immunomodulatory effect of CBD is given by its stimulatory action on IL-12 [59] in association with an inhibitory effect on IL-10 [59], TNF-alpha and IL-17 [29,37]. By considering that MLT stimulates IL-2 production from Th1 cells and promotes IL-12 secretion from dendritic cells in addition to an inhibitory effect on TNF-alpha and IL-6 production [34], as well as on IL-17 and TGF-beta at least in some clinical conditions [44], the simple non-toxic and non-expensive association of MLT with CBD may already constitute an effective neuroendocrine approach the modulate host immunoinflammatory response. The importance of controlling an eventual excessive host immunoinflammatory reaction, due to an abnormal endogenous secretion of inflammatory cytokines in the absence of an adequate concomitant production of anti-inflammatory cytokines, has dramatically emerged with the planetary disease of Covid-19 infection [23], involving the whole world for the first time of human history. ...
... Obviously, a neuroimmune approach in the treatment of human systemic diseases requires a new diagnostic profile, with the proposal of new laboratory examinations, which are generally excluded from the common clinical practices. This new diagnostic approach has at least to include the measurement of the main cytokines, in particular IL-2, IL-6, TNF-alpha, IL-17 and TGF-beta in cancer, IL-17, TGF-beta, IL-2, IL-6 and TNF-alpha in autoimmune pathologies, the evaluation of the circadian light/ dark rhythm of MLT on blood or in an easier manner of the urinary levels of the main MLT metabolite 6-sulfatoxymelatonin, and the investigation of the functional status of the endocannabinoid system, which may be assesses by detecting AEA and 2-AG blood levels, or in simpler manner by measuring the blood levels of FAAH [29,44]. The evidence of high levels of FAAH can be considered as the expression of an endogenous cannabinoid deficiency. ...
... MOI: multiplicity of infection, OMV: outer membrane vesicle, Sup: supernatant. 57 . Therefore, the inactivated A. muciniphila might be considered a paraprobiotic candidate for the treatment of IBS, especially in conditions that the treatment of live bacteria might exacerbate the inflammation condition. ...
... www.nature.com/scientificreports/ the mucus layer and counteract the fat mass development56 .Russo et al. (2004) reported that CB1 deficiency might lead to some disorders, such as inflammatory bowel diseases (known as irritable bowel syndrome [IBS]), migraine, fibromyalgia, and psychological disorders ...
Article
Full-text available
This study aimed to investigate the effects of active and heat-inactivated forms of Akkermansia muciniphila, bacterium-derived outer membrane vesicles (OMVs), and cell-free supernatant on the transcription of endocannabinoid system (ECS) members, including cannabinoid receptors 1 and 2 (CB1 and CB2), fatty acid amide hydrolase (FAAH), and peroxisome proliferator-activated receptors (PPARs) genes (i.e., α, β/δ, and δ) in Caco-2 and HepG-2 cell lines. After the inoculation of A. muciniphila in brain heart infusion enriched medium, OMVs and cell-free supernatant were extracted. For the investigation of the effects of bacteria and its derivatives on the expression of ECS and PPARs genes, the aforementioned cells were treated by active and heat-inactivated bacteria, OMVs, and cell-free supernatant. Quantitative real-time polymerase chain reaction analysis revealed that both forms of the bacterium, bacterial-derived OMVs, and cell-free supernatant could affect the expression of CB1, CB2, FAAH, and PPARs genes (i.e., α, β/δ, and δ) significantly (P < 0.05). Considering the engagement of the aforementioned genes in metabolic pathways, it might be suggested that both forms of the bacterium, OMVs, and cell-free supernatant might have the potential to serve as a probiotic, paraprobiotic, and postbiotic candidate to prevent obesity, metabolic disorders, and liver diseases.
... Endocannabinoid deficiency was first postulated to have a role in migraine pathophysiology in the early 2000s. 87 This hypothesis was supported by subsequent studies that showed higher platelet activity of both FAAH and anandamide transporter in female patients with migraine as compared with controls. 65 A positron emission tomography (PET) study showed increased CB1 binding in specific brain areas implicated in pain processing in subjects with episodic migraine (EM). ...
Article
Full-text available
Background: Migraine is a complex and highly disabling neurological disease whose treatment remains challenging in many patients, even after the recent advent of the first specific-preventive drugs, namely monoclonal antibodies that target calcitonin gene-related peptide. For this reason, headache researchers are actively searching for new therapeutic targets. Cannabis has been proposed for migraine treatment, but controlled clinical studies are lacking. A major advance in cannabinoid research has been the discovery of the endocannabinoid system (ECS), which consists of receptors CB1 and CB2; their endogenous ligands, such as N-arachidonoylethanolamine; and the enzymes that catalyze endocannabinoid biosynthesis or degradation. Preclinical and clinical findings suggest a possible role for endocannabinoids and related lipids, such as palmitoylethanolamide (PEA), in migraine-related pain treatment. In animal models of migraine-related pain, endocannabinoid tone modulation via inhibition of endocannabinoid-catabolizing enzymes has been a particular focus of research. Methods: To conduct a narrative review of available data on the possible effects of cannabis, endocannabinoids, and other lipids in migraine-related pain, relevant key words were used to search the PubMed/MEDLINE database for basic and clinical studies. Results: Endocannabinoids and PEA seem to reduce trigeminal nociception by interacting with many pathways associated with migraine, suggesting a potential synergistic or similar effect. Conclusions: Modulation of the metabolic pathways of the ECS may be a basis for new migraine treatments. The multiplicity of options and the wealth of data already obtained in animal models underscore the importance of further advancing research in this area. Multiple molecules related to the ECS or to allosteric modulation of CB1 receptors have emerged as potential therapeutic targets in migraine-related pain. The complexity of the ECS calls for accurate biochemical and pharmacological characterization of any new compounds undergoing testing and development.
... Korkeammilla pitoisuuksilla yhdiste voi hidastaa endokannabinoidijärjestelmän entsyymien hajoamista COX-1 ja COX-2 reseptorien kautta(Pacher ja Kunos 2013;Kendall ja Alexander 2017.) Kannabinoidien ja kannabinoidihappojen syöminen voi olla avain endokannabinoidijärjestelmän puutostilojen aiheuttamien kroonisten sairauksien, kuten migreenin, ärtyvän suolen oireyhtymän, glaukooman, fibromyalgian ja potentiaalisesti monen muun sairauden hoidossa(Russo 2008).Eniten kannabinoideista on tutkittu THC:tä ja CBD:tä. Tetrahydrokannabinoli (THC) on hampun psykoaktiivinen yhdiste. ...
Thesis
Full-text available
There was a demand for marketing material and knowledge base for the cannabinoid products that the client Hamppumaa is reselling. The goal was to clarify the effects, possibilities, production, refining, markets and media conversation. There was not any finnish clarification about the cannabinoid industry so we wanted to translate what cannabinoid products are and what are their possibilities. The implementation method was a literature review on scientific studies and media articles. The results clarified the effects of cannabinoids, production related legislation in Finland and abroad, different processing methods and refining possibilities. Also including observations on cannabinoid markets and recent media conversations. Conclusion stated that cannabinoid products have market potential, health effects, changing legislative sitution and industrial possibilities in Finland.
... The anti-nociceptive effects of endocannabinoids are thought to be mediated mainly through the activation of cannabinoid receptor type 1 (CB1) [198]. Localization of CB1 receptors along the trigeminal tract and trigeminal afferents [199,200] suggests that the endocannabinoid system can modulate the neurogenic-induced migraine [201]. Clinical data suggested that in migraine patients, the endocannabinoid levels are lower [202,203]. ...
Article
Full-text available
Migraine is a primary headache disorder characterized by a unilateral, throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors, and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses, including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This narrative review discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.
... The anti-nociceptive effects of endocannabinoids are thought to be mediated mainly through the activation of cannabinoid receptor type 1 (CB1) [198]. Localization of CB1 receptors along the trigeminal tract and trigeminal afferents [199,200] suggests that the endocannabinoid system can modulate the neurogenic-induced migraine [201]. Clinical data suggested that in migraine patients, the endocannabinoid levels are lower [202,203]. ...
Preprint
Full-text available
Migraine is a primary headache disorder characterized by unilateral throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This review article discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease. Graphical abstract Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 3 November 2021
Article
Full-text available
The endocannabinoid system (ECS) plays an important role in pain processing and modulation. Since the specific effects of endocannabinoids within the orofacial area are largely unknown, we aimed to determine whether an increase in the endocannabinoid concentration in the cerebrospinal fluid (CSF) caused by the peripheral administration of the FAAH inhibitor URB597 and tooth pulp stimulation would affect the transmission of impulses between the sensory and motor centers localized in the vicinity of the third and fourth cerebral ventricles. The study objectives were evaluated on rats using a method that allowed the recording of the amplitude of evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation and URB597 treatment. The amplitude of ETJ was a measure of the effect of endocannabinoids on the neural structures. The concentrations of the endocannabinoids tested (AEA and 2-AG) were determined in the CSF, along with the expression of the cannabinoid receptors (CB1 and CB2) in the tissues of the mesencephalon, thalamus, and hypothalamus. We demonstrated that anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), was significantly increased in the CSF after treatment with a FAAH inhibitor, while tooth pulp stimulation had no effect on the AEA and 2-AG concentrations in the CSF. We also found positive correlations between the CSF AEA concentration and cannabinoid receptor type 1 (CB1R) expression in the brain, and between 2-AG and cannabinoid receptor type 2 (CB2R), and negative correlations between the CSF concentration of AEA and brain CB2R expression, and between 2-AG and CB1R. Our study shows that endogenous AEA, which diffuses through the cerebroventricular ependyma into CSF and exerts a modulatory effect mediated by CB1Rs, alters the properties of neurons in the trigeminal sensory nuclei, interneurons, and motoneurons of the hypoglossal nerve. In addition, our findings may be consistent with the emerging concept that AEA and 2-AG have different regulatory mechanisms because they are involved differently in orofacial pain. We also suggest that FAAH inhibition may offer a therapeutic approach to the treatment of orofacial pain.
Article
Characterised by chronic widespread musculoskeletal pain, generalised hyperalgesia, and psychological distress, fibromyalgia (FM) is a significant unmet clinical need. The endogenous cannabinoid system plays an important role in modulating both pain and the stress response. Here, we appraise the evidence, from preclinical and clinical studies, for a role of the endocannabinoid system in FM and the therapeutic potential of targeting the endocannabinoid system. While many animal models have been used to study FM, the reserpine-induced myalgia model has emerged as the most translatable to the clinical phenotype. Inhibition of fatty acid amide hydrolase (FAAH) has shown promise in preclinical studies, ameliorating pain- and anxiety-related behaviour, and not associated with the development of tolerance. Clinically, there is evidence for alterations in the endocannabinoid system in patients with FM, including single nucleotide polymorphisms and increased levels of circulating endocannabinoids and related N-acylethanolamines. Single entity cannabinoids, cannabis, and cannabis-based medicines in patients with FM show promise therapeutically but limitations in methodology and lack of longitudinal studies to assess efficacy and tolerability preclude the current recommendation for their use in patients with FM. Gaps in the literature that warrant further investigation are discussed, particularly the need for further development of animal models with high validity for the multifaceted nature of FM, balanced studies to eliminate sex-bias in preclinical research, and ultimately, better translation between preclinical and clinical research.
Conference Paper
Full-text available
The need to develop and improve accounting in the Republic of Azerbaijan is due to a number of external and internal factors. The country's accession to the ongoing and deepening economic integration in the world, the strengthening of foreign investment flows, the expansion of enterprises' relations with foreign companies, the improvement of accounting, reporting and analysis, and the development of international standards are external factors that determine adaptation. In the emerging single economic area, in international markets, it is the information provided by accounting, analysis, auditing and reporting. The formation of this information in a way that everyone can understand is consistent with the theoretical and methodological foundations of global accounting and reporting, including accounting, analysis and reporting on current assets. However, it is theoretically and practically incorrect to attribute the need to improve the accounting and analysis of current assets and bring them into line with international standards solely on external factors. The point is that the existing system of accounting, analysis and reporting in this area has certain shortcomings and deficiencies from a theoretical, methodological and practical point of view. In general, the current state of accounting, analysis and reporting of short-term assets does not fully correspond to the modern dynamics and characteristics of a market economy, and its development. Thus, it becomes an objective necessity to conduct a comprehensive study of the current state of accounting, analysis and reporting of current assets in the country, to improve it and bring it in line with international standards.
Chapter
The endocannabinoid system (ECS) was discovered in the early 1990s and is one of the most important neuroregulatory systems in the body. The ECS is responsible for homeostasis of most systems in the body. At a simplistic level, it is composed of endogenous ligands called endocannabinoids, cannabinoid receptors (CB1 and CB2 receptors), and enzymes that synthesize and degrade them. However, the ECS is actually more complex than this and there are other receptors and endocannabinoid-like substances involved in the ‘extended ECS’. CB1 receptors are particularly concentrated in the central nervous system and CB2 receptors are particularly concentrated in cells and tissues/organs of the immune system. However, cannabinoid receptors are also widely distributed throughout the body. In the nervous system, the classical understanding is that endocannabinoids are synthesized on demand in postsynaptic neurons and act as retrograde messengers, binding with cannabinoid receptors on presynaptic neurons to reduce neurotransmitter release from the presynaptic neuron. It is now known that there are also intracellular reservoirs and transporters of endocannabinoids. The ECS is critically involved in brain development, from the fetus through to adulthood. Dysfunction including deficiency of the ECS has been associated with a range of pathological disorders, including mental health conditions. The ECS plays a key role in the regulation of our mind and emotions and our reaction to stress. It is involved with the corticolimbic system and the HPA axis, both of which are key systems involved in regulation of stress and emotions. This chapter gives an overview of the ECS, as an understanding is necessary to later understand how medicinal cannabis may work in alleviating mental health disorders.
Chapter
Full-text available
The herb cannabis is derived from the Old World species Cannabis sativa L. Cannabis indica and C. ruderalis may also merit species status. Cannabis has a history as an analgesic agent that spans at least 4000 years, including a century of usage in mainstream Western medicine. Quality control issues, and ultimately political fiat eliminated this agent from the modern pharmacopoeia, but it is now resurgent. The reasons lie in the remarkable pharmacological properties of the herb and new scientific research that reveals the inextricable link that cannabinoids possess with our own internal biochemistry. In essence, the cannabinoids form a system in parallel with that of the endogenous opioids in modulating pain. More important, cannabis and its endogenous and synthetic counterparts may be uniquely effective in pain syndromes in which opiates and other analgesics fail.
Article
Background: Preliminary studies suggested that delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa L., might be effective in the treatment of Tourette syndrome (TS). This study was performed to investigate for the first time under controlled conditions, over a longer-term treatment period, whether THC is effective and safe in reducing tics in TS. Method: In this randomized, double-blind, placebo-controlled study, 24 patients with TS, according to DSM-III-R criteria, were treated over a 6-week period with up to 10 mg/day of THC. Tics were rated at 6 visits (visit 1, baseline; visits 2-4, during treatment period; visits 5-6, after withdrawal of medication) using the Tourette Syndrome Clinical Global Impressions scale (TS-CGI), the Shapiro Tourette- Syndrome Severity Scale (STSSS), the Yale Global Tic Severity Scale (YGTSS), the self-rated Tourette Syndrome Symptom List (TSSL), and a videotape-based rating scale. Results: Seven patients dropped out of the study or had to be excluded, but only 1 due to side effects. Using the TS-CGI, STSSS, YGTSS, and video rating scale, we found a significant difference (p < .05) or a trend toward a significant difference (p < .05) between THC and placebo groups at visits 2, 3, and/or 4. Using the TSSL at 10 treatment days (between days 16 and 41) there was a significant difference (p < .05) between both groups. ANOVA as well demonstrated a significant difference (p = .037). No serious adverse effects occurred. Conclusion: Our results provide more evidence that THC is effective and safe in the treatment of tics. It, therefore, can be hypothesized that the central cannabinoid receptor system might play a role in TS pathology.
Article
EDITOR—Campbell et al's paper on whether cannabinoids are effective and safe in the management of pain purports to be qualitative and systematic,1 but it is neither. Because it focused on two clinically questionable synthetic cannabinoids and oral delta-9-tetrahydrocannabinol (THC) without providing any focus on the synergistic components of herbal cannabis, and examined only certain facets of the broad topic of pain, it ensured that a conclusion of limited efficacy was reached. That is not news. What is surprising, in contrast, is that the authors chose to broaden the alleged impact of their limited investigation to relegate the use of cannabis and cannabinoids to a back seat in future analgesic applications. This contention is not supported by their limited data. I see nothing published about pioneering British doctors and their clinical successes with cannabis extracts in a myriad of painful conditions between 1840 and 1940.2-4 I see virtually nothing of modern scientific studies showing the multifactorial benefits of cannabis on a range of neurotransmitter systems, which I have reviewed.5 No mention is made of bureaucratic and political obstructions to clinical research into cannabis; one cannot show results when the requisite studies are not permitted. Thus until recently we have been left with an overwhelming (but ignored) body of anecdotal evidence from patients and their doctors. What is truly newsworthy here is that the BMJ has ignored peer review and editorial standards in a scandalous manner. The popular media have seized the opportunity, and in the process valuable laboratory and clinical research, and their funding, in analgesia and pain control have been severely compromised. Great shame accrues to the journal as a result. Instead of probity we have propaganda. Footnotes Competing interests Professor Russo has been a scientific adviser to GW Pharmaceuticals (a manufacturer of cannabis-based medicine extracts), which has reimbursed expenses for travel with regard to visits and clinical research. He is also the editor in chief of Journal of Cannabis Therapeutics.
Article
Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endo- genous substances - the endocannabinoids - that activate specific cell surface receptors. Cannabi- noids exert palliative effects in cancer patients. For example, they inhibit chemotherapy-induced nausea and vomiting, stimulate appetite and inhibit pain. In addition, cannabinoids inhibit tumor growth in laboratory animals. They do so by modulating key cell signaling pathways, thereby in- ducing antitumoral actions such as the apoptotic death of tumor cells as well as the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds as they can kill tumor cells without significantly affecting the viability of their non-transformed counter- parts. On the basis of these preclinical findings a pilot clinical study of ∆ 9 -tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has recently been run. The fair safety profile of THC, together with its possible growth-inhibiting action on tumor cells, may set the ba- sis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.