REVIEW Open Access
Clinical Endocannabinoid Deﬁciency Reconsidered:
Current Research Supports the Theory in Migraine,
Fibromyalgia, Irritable Bowel, and Other
Ethan B. Russo*
Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack ob-
jective signs and remain treatment resistant. Foremost among these are migraine, ﬁbromyalgia, and irritable
bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured
the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with
substandard beneﬁt. The commonality in symptomatology in these conditions displaying hyperalgesia and cen-
tral sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid
deﬁciency might characterize their origin. Its base hypothesis is that all humans have an underlying endocanna-
binoid tone that is a reﬂection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and
2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid re-
ceptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes
deﬁcient and productive of pathophysiological syndromes. When ﬁrst proposed in 2001 and subsequently, this
theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by
the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided
symptomatic beneﬁt. However, objective proof and formal clinical trial data were lacking. Currently, however,
statistically signiﬁcant differences in cerebrospinal ﬂuid anandamide levels have been documented in migrai-
neurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder.
Additional studies have provided a ﬁrmer foundation for the theory, while clinical data have also produced ev-
idence for decreased pain, improved sleep, and other beneﬁts to cannabinoid treatment and adjunctive lifestyle
approaches affecting the ECS.
Key words: anandamide; anorexia nervosa; cannabidiol; cannabinoids; depression; endocannabinoids; ﬁbro-
myalgia; Huntington disease; irritable bowel syndrome; migraine; motion sickness; multiple sclerosis; Parkinson
disease; post-traumatic stress disorder; prebiotics; THC
Introduction: Background History and Theory
of Clinical Endocannabinoid Deﬁciency
The theory of clinical endocannabinoid deﬁciency
(CED) was presented in 2001 in two publications,
but more thoroughly explored in 2004
in an article
that has subsequently been cited frequently in the lit-
The theory of CED was based on the con-
cept that many brain disorders are associated with
neurotransmitter deﬁciencies, affecting acetylcholine
in Alzheimer’s disease, dopamine in parkinsonian syn-
dromes, serotonin and norepinephrine in depression,
and that a comparable deﬁciency in endocannabinoid
PHYTECS, Vashon Island, Washington.
*Address correspondence to: Ethan B. Russo, MD, PHYTECS, 1875 Century Park East, Suite 2250, Los Angeles, CA 90067, E-mail: email@example.com
ªEthan B. Russo 2016; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work
is properly credited.
Cannabis and Cannabinoid Research
Volume 1.1, 2016
levels might be manifest similarly in certain disorders
that display predictable clinical features as sequelae of
All humans possess an underlying endocannabinoid
tone that reﬂects of levels of anandamide (AEA) and 2-
arachidonoylglycerol (2-AG), the centrally acting endo-
cannabinoids, their synthesis, catabolism, and the relative
density of cannabinoid receptors in the brain. If endo-
cannabinoid function were decreased, it follows that a
lowered pain threshold would be operative, along with
derangements of digestion, mood, and sleep among the
almost universal physiological systems subserved by the
endocannabinoid system (ECS).
The CED theory also
posits that such deﬁcienciescouldariseduetogenetic
orcongenitalreasonsorbeacquired due to intercurrent
injury or disease that consequently produces characteris-
tic pathophysiological syndromes with particular symp-
The greatest evidence for CED is present for mi-
graine, ﬁbromyalgia, and irritable bowel syndrome
A strong case can be advanced for unifying
pathophysiological trends in the three conditions:
All manifest hyperalgesic states must be clinically
diagnosed based on subjective criteria as all lack
characteristic tissue pathology or easily accessible
objective laboratory ﬁndings
All are diagnoses of exclusion that often generate
extensive negative diagnostic work-ups
They display elevated incidence of anxiety and de-
pression (in a chicken vs. egg dilemma) and have
been labeled psychosomatic in origin or worse,
wastebasket diagnoses, at one time or another by
Comorbidity is quite clear in the three diagnoses.
Primary headaches co-occurred in 97% of 201 ﬁbro-
35.6% of 101 chronic daily head-
ache (transformed migraine) subjects also ﬁt
clinical criteria of ﬁbromyalgia,
and 31.6% of IBS
subjects were also diagnosable with ﬁbromyalgia,
while 32% of ﬁbromyalgia patients also ﬁt for IBS
While some patients suffer from only one of these
syndromes, lifetime risk to develop another or all
three is quite common (Fig. 1).
An extensive list of other disorders previously cited
that may fall under the CED rubric included
failure to thrive,
phantom limb pain, infantile colic, glau-
unexplained fetal wastage (repetitive miscarriages),
post-traumatic stress disorder (PTSD),
and possibly many others. All display as yet
unfathomed pathophysiological features and remain
treatment resistant. Might their underlying nature
have been missed? Recently, in a seminal article on
the ECS and its optimization,
the authors added sup-
port for these and various other conditions.
Materials and Methods
Standard searches were undertaken of the PubMed/
National Library of Medicine database for the listed
keywords and references from pertinent literature for
pertinence to clinical cannabinoid deﬁciency.
IBS, CED, and the Microbiome–Gut–Brain Axis
IBS, also known as spastic colon, is a functional disor-
der characterized by gastrointestinal (GI) pain, spasm,
discomfort, and altered bowel movements, either pre-
dominantly diarrhea, predominantly constipation, or
alternating between those states. Attacks are highly
correlated with anxiety, but debate continues as to
which incites the other. Individual episodes may be
triggered by some speciﬁc foods or dietary indiscre-
tions such as overeating on holidays. While frequently
assessed as a life-long condition,
it is clear that signif-
icant gastrointestinal insults such as food poisoning or
antibiotic administration may generate attacks that
persist, often indeﬁnitely. IBS is the most frequent diag-
nosis in gastroenterology practices in the United States,
FIG. 1. Diagram depicting comorbidity of
migraine, ﬁbromyalgia, and irritable bowel
Russo; Cannabis and Cannabinoid Research 2016, 1.1
with prevalence in the Western world of 10–15%.
an idiopathic disorder, no physical signs are pathogno-
monic, and even diagnostic procedures such as labo-
ratory tests, including those for gluten enteropathy,
colonoscopy, or barium studies, most often fail to
identify other causes,
but more formal Rome criteria
have been established.
Those authors characterized
the status of IBS as (p. 409) a disorder of unknown or-
igin being treated by agents with an unknown mecha-
nism of action. It has been posited that IBS represents a
visceral hypersensitivity, with features of GI allodynia
A seminal review of the ECS and
its relationship with the GI tract appeared that year.
To summarize, GI propulsion, secretion, and inﬂamma-
tion in the gut are all modulated by the ECS, providing a
rationale for cannabinoids as treatment candidates for
As examples, GI propulsion is under tonic con-
trol of the ECS,
and cannabis was one of the ﬁrst ef-
fective clinical interventions in the 19th century for
the intense secretory diarrhea associated with cholera,
a ﬁnding which was more recently validated with mod-
The use, by its sufferers, of cannabis-based agents to
treat IBS has eventuated in large part due to the unfortu-
nate fact that conventional treatment with anticholinergics,
opioids, and antidepressants has been quite suboptimal,
while three dedicated agents have been withdrawn from
certain markets after prior regulatory approval. Two 5-
antagonists, alosetron and cilansetron, were asso-
ciated with ischemic colitis, while tegaserod, a 5-HT
agonist, produced cardiovascular adverse events.
Additional support for the ECS as a key modulator of
GI function was provided in an examination of circular
muscle ﬁbers from colonoscopic biopsies of surgical spec-
imens from 31 normal patients.
AEA colocalized with
cholinergic receptors in normal colon and inhibited the
cholinergic contractile force of circular and longitudi-
nal muscles through a non-CB
mechanism or possibly
an alternative cannabinoid mechanism not mediated
. It was posited that inﬂammatory and
disease states in the gut rendered the ECS more func-
A 3.5-fold elevation in TRPV1-immunoreactive
nerve ﬁbers was observed in biopsies from IBS sufferers
compared with controls ( p<0.0001).
observed (p. 923) that the increased TRPV1 nerve ﬁ-
bers may contribute to visceral hypersensitivity and
pain in IBS and provide a novel therapeutic target.
Thus, a rationale exists for therapeutic interventions
that would boost AEA levels or desensitize TRPV1,
such as cannabidiol (CBD), to treat the condition.
Although fatty acid amide hydrolase (FAAH) inhibi-
tion of CBD has been questioned by some, its ability
to raise serum AEA levels was clearly indicated when
administered in high doses to schizophrenic patients.
Genetic variation affecting endocannabinoid metabo-
lism was observed in diarrhea-predominant IBS pa-
THC (dronabinol) treatment slowed colonic
transit time in subjects harboring the CNRI rs806378
CT/TT genotype. Subsequently, a statistically signiﬁcant
association of this gene with colonic transit in IBS with
diarrhea (IBS-D) was demonstrated ( p=0.014).
observed (p. G559) that CB
nisms modify colonic transit and sensation and may in-
ﬂuence the development of symptoms in Caucasian
patients with IBS, particularly IBS-D.
Unfortunately, while many patient surveys have
touted beneﬁts of cannabinoid treatment of IBS symp-
and abundant anecdotal support is evident on
the Internet, little actual clinical work has been accom-
plished. In a randomized controlled trial (RCT) of 52
normal patients taking single doses of 7.5 mg of THC
versus placebo, the drug increased colonic compliance
(p=0.045) and inhibited postprandial colonic tone
(p=0.048) and fasting and postprandial phasic pres-
sure ( p=0.008), with a trend toward relaxation of fast-
ing colon tone ( p=0.096).
Another study focused on
visceral sensitivity to rectal distention as measured by a
barostat in normal (N=12) versus IBS (N=10) patients
after administration of THC.
No signiﬁcant differ-
ences were noted, but adverse events were reported in
100% of participants at the 10 mg dosage. A third
small (23 IBS patients) trial of synthetic THC for a
brief interval (2 days) showed no change in transit
More formal studies with whole cannabis ex-
tracts would be illuminating.
Additional interventions may be practical on the nu-
tritional front utilizing new knowledge of the utility of
probiotics and prebiotics. A direct effect of Lactobacil-
lus acidophilus NCFM strain through oral administra-
tion to induce CNR2 mRNA expression above that of
resting human HT-29 epithelial cells ( p<0.01) was
demonstrated along with an enhancement of morphine
antinociceptive effect in rats ( p<0.001), which was
inhibited by administration of the CB
AM-630 ( p<0.001).
A review of human studies of
probiotic supplements to treat IBS revealed that 34/42
trials demonstrated beneﬁcial effects for one or more
end-points or target symptoms (pain, discomfort, bloat-
ing, distention, laboratory parameters).
Russo; Cannabis and Cannabinoid Research 2016, 1.1
of the microbiome–gut–brain axis in IBS is underscored
by the recent ﬁnding that THC altered the microﬂoral
balance in obese diet-induced obese mice, affecting the
Firmicutes:Bacteroidetes ratio ( p=0.021) and preventing
optimal gut health without pain and with maintenance of
appropriate body weight seems to require a complex in-
terplay between diet, enteric ﬂora, and endocannabinoid
Experimental models have obvious limitations, and
contrary ﬁndings are always possible. A recent study
demonstrated in a mouse model of accelerated GI transit
that palmitoylethanolamide, an entourage endocannabi-
noid, indirectly activated CB
receptors only under con-
ditions in which AEA or the receptors were upregulated,
not deﬁcient. Furthermore, it is unfortunate that labora-
tory measures of serum or tissue endocannabinoid levels
have not been systematically examined in IBS.
Migraine and CED
Migraine is an extremely prevalent headache syndrome
affecting 14% of Americans, with a 3:1 female:male ratio
and $20 billion annual cost in that country.
thor has previously reported on migraine’s treatment
and two major reviews have recently
Migraine is far more complex than merely
cranial pain. It has a genetic predilection and female pre-
dominance and presents as a predominantly hemicranial
beating headache associated with unusual associated
manifestations: nausea, photophobia, and phonophobia,
with hormonal and environmental triggers.
The possible relationship of migraine with the ECS
is highlighted by numerous ﬁndings. Anandamide
produced serotonin receptor responses consisting of
89% potentiation of 5-HT
and 36% inhibition of
ﬁndings that have been associated with
proﬁles of effective pharmacological migraine inter-
ventions that would seem to support respective activ-
ity in acute and chronic migraine (CM), respectively.
The migraine epiphenomena of photophobia and pho-
nophobia suggest an overactive sensory hyperalgesia,
just the kind of homeostatic imbalance that the ECS
tends to correct in central nervous system (CNS) func-
The periaqueductal gray matter is a putative mi-
graine generator in which AEA is tonically active,
producing analgesia when administered or hyperalge-
sia when CB
is pharmacologically blocked.
A great deal of additional support for the integral role
of the ECS in migraine pathophysiology has been pro-
vided by a series of investigations linking endocannabi-
noids to the trigeminovascular system, which many
consider to lie at the root of its pathophysiology. The
resulted in several pertinent ﬁndings:
AEA diminished blood vessel dilation in the dura mater
induced by calcitonin gene-related peptide (CGRP)
30%, capsaicin 45%, and nitric oxide (NO) 40%. Addi-
tionally, AEA acted presynaptically to prevent release
of NO by CGRP in dural artery smooth muscle. AEA
also was released in tonic manner and displayed modu-
latory activity in the trigeminovascular system.
A subsequent article focused on vascular phenomena
associated with migraine.
AEA caused dose-dependent
dural vessel dilation that was diminished by capsazepine,
nist. (While the vascular effects of this and the prior
study may appear contradictory, it should be noted
that migraine produces vasoconstriction or vasodilation
in different phases and that these are epiphenomena of
the disorder, rather than its etiology.) The concentration
of AEA that produced these ﬁndings was far higher than
that required to activate CB
that repetitive administration with a TRPV1 agonist such
could conceivably desensitize the receptor
and thus alleviate these pathophysiological mecha-
nisms, much as capsaicin has successfully reduced
peripheral neuropathic pain with regular cutaneous
administration. Capsaicin has even been utilized in-
tranasally as an acute migraine treatment,
and it is
thus reasonable to consider CBD as a less noxious al-
ternative desensitizing intervention.
A third publication examined trigeminovascular
with ﬁndings that WIN 55,212-
2, a potent CB
agonist, inhibited trigeminocervical
complex A and C-ﬁber afferent activity, which was ab-
rogated by SR141716A, a CB
inverse agonist. How-
ever, this ﬁnding was only obtained with AEA after
prior TRPV1 blockade by capsazepine. These ﬁndings
support possible clinical application of CB
in migraine and cluster headache, although the authors
warned of psychoactive sequelae of agents such as THC.
In an animal model of migraine,
nitroglycerin-induced neuronal activation in the nucleus
trigeminalis caudalis and area postrema, the latter being
an emetic chemoreceptor. There was likewise an induc-
tion of expression of the immediate early gene transcrip-
tion factor Fos in the hypothalamic paraventricular and
supraoptic nuclei, in the parabrachial nucleus, and in the
brainstem periaqueductal gray matter of the brainstem.
These ﬁndings reinforce an important role of the ECS in
generation of migraine episodes.
Russo; Cannabis and Cannabinoid Research 2016, 1.1
Various studies in Italy have focused on the etiolog-
ical relationship of platelets with migraine in affected
patients. In one
of the studies, increased function in
AEA membrane transporter and AEA hydrolase (now
known as fatty acid amidohydrolase [FAAH], the en-
zyme that catabolizes AEA) in platelets of women with
migraine without aura was observed in comparison
with patients with episodic tension headache or con-
trols with no headaches. Interestingly, there were no
differences in CB
receptor density in the groups,
but AEA hydrolysis was elevated in platelets of mi-
graine sufferers. Consequent decreased serum AEA
levels could theoretically lower the pain threshold in
In another study,
female and male migraineurs
both displayed lower FAAH and AEA membrane
transporter platelet activity, hypothesized as a possible
adaptive response to CM or a reaction to overuse of
pain killers known as analgesic rebound. An additional
showed that 2-AG and AEA levels were both
profoundly reduced in the platelets of patients with ep-
isodic migraine without aura (N=20) and CM (N=20)
versus controls (N=20) ( p<0.0001).
Perhaps the strongest evidence of the existence of
CED in migraine or any disorder comes from a study
that assayed cerebrospinal ﬂuid (CSF) AEA levels in
15 chronic migraineurs versus 20 controls with a phe-
nomenal statistically signiﬁcant difference ( p<0.0001)
(Fig. 2). The authors opined concerning what they
termed a system failure in migraine (p. 1387):
Reduced AEA levels in the CSF of CM [chronic migraine] pa-
tients support the hypothesis of the failure of this endogenous
CB [cannabinoid] system in CM, which seems to be related to
increased CGRP and NO production in this pathological con-
dition. This ﬁnding might be due to a failure of the inhibitory
role of the endocannabinoid AEA on the trigeminovascular
THC (1–20 lM) and other CB
dependently diminished cortical spreading depression
amplitude, duration, and propagation velocity ( p<0.001)
in a rat brain model, supporting its ability to inhibit
the trigeminovascular in migraine with aura.
A clinical study examined 27 medication-overuse
headache patients, a common precipitant of migraine
Before treatment, patients displayed
decreased temporal summation thresholds, increased
pain sensation, and reduced platelet FAAH (the enzyme
that breaks down AEA) expression versus controls.
After medication withdrawal treatment and elimination
of analgesic rebound effects, FAAH activity, and tem-
poral summation thresholds signiﬁcantly normalized
(both p=0.001), supporting an etiological ECS dys-
function in these patients.
In subsequent experiments in mice,
injection of nitroglycerine induced mechanical hyperal-
gesia that was almost totally eliminated by FAAH dele-
tion or administration of FAAH inhibitors ( p<0.0001).
Additional supportive data on the migraine-ECS rela-
tionship are derived from genetic investigation. The CB
gene, CNR1 mapped to chromosome 6q14-15, was
linked to migraine through haplotypic tagging with
FIG. 2. Anandamide levels in cerebrospinal ﬂuid of chronic migraine patients versus controls, adapted from
data obtained from Sarchielli et al.
Russo; Cannabis and Cannabinoid Research 2016, 1.1
high signiﬁcance ( p=0.008) and indicative of a genetic
effect altering trigeminovascular activation.
gest linkage was to HT6 haplotype ( p=0.002), which
correlated highly with migraine symptoms of photo-
phobia >nausea >disability. Migraineurs also showed
greater degrees of neuroticism ( p<0.001), depression
(p<0.001), and reported drug/alcohol abuse ( p<
0.005). Of late, many pharmaceutical companies have
pursued development of antibodies aimed at CGRP as
a therapeutic target in migraine prophylaxis,
mains to be seen whether this represents a more funda-
mental target than strategies focusing on the ECS.
Until recently, only case reports and surveys of use
of THC and cannabis and its effects on migraine have
but a more formal observational
trial has been reported
from a cannabis-oriented clinic
in the state of Colorado. Among 120 adults with mi-
graine for whom cannabis prophylaxis was recommen-
ded, and of which 67.8% had previously used cannabis,
the frequency of headache diminished from 10.4 to 4.6
attacks per month (p<0.0001) (Fig. 3). Overall, 85.1%
had decreased migraine frequency, with 39.7% reporting
positive effects: prevention of or reduced headache fre-
quency (19.8%) or aborted headache (11.6%) in this
selected and uncontrolled population employing a mix-
ture of administration techniques with unanalyzed but
presumably high-THC cannabis.
It is worth remembering that cannabis was a mainstay
of treatment of migraine in Europe and North America
for a century between 1843 and 1943,
porting claims of a high degree of efﬁcacy of cannabis
treatment in both acute and prophylactic treatments of
migraine. Further study utilizing modern techniques
and standardized preparations with low THC and
higher titers of CBD in proper RCTs is long overdue.
Focus on Fibromyalgia
Fibromyalgia was probably ﬁrst described by Sir Wil-
as ﬁbrositis, a condition characterized
as soft tissue pain that could wander in the body, and
which was aggravated by overuse. In the 1980s, ﬁbro-
myalgia became the preferred term due to a failure to
identify inﬂammation or other objective changes in tis-
sue biopsies from affected patients. Formal diagnostic
parameters (Rome Criteria) were established thereafter.
While a recent report indicated the presence of small
ﬁber neuropathy in a subset of patients with ﬁbromyal-
creating possible diagnostic confusion,
this ﬁnding by no means explains all such cases. Fibro-
myalgia is noteworthy for its characteristic painful
nodules dubbed as trigger points that are particularly
prevalent in the shoulder and neck that are frequently
of sufﬁcient severity to limit physical activity. The dis-
order has a clear association with depression and anx-
iety, but debate surrounds the timing and relationship
of these comorbidities. Like migraine, it is more preva-
lent in women and invariably disrupts sleep. The disor-
der remains controversial in some quarters, but it is
nonetheless the most common diagnosis in American
Many authorities now posit
a central sensitization consistent with neuropathic pain
at the root of the syndrome.
In Italy, it was noted
that ﬁbromyalgia, like migraine, was associated with sec-
ondary hyperalgesia, that is, a lowered threshold to pain
in areas adjacent to the primarily affected parts,
which the authors suggested pharmacological NMDA
blockade for what they interpreted as a deﬁcit in seroto-
nergic analgesia. That same year, hyperalgesia was ob-
served in association with central endocannabinoid
hypofunction in the spinal cord and that endocannabi-
noids reduced associated hyperalgesia,
ECS a prime target and CED a rational explanation.
The authors proposed that cannabinoid treatments
would be indicated for various maladies driven by a
primary afferent barrage, which would include visceral
hyperalgesia (as hypothesized in IBS), allodynia associ-
ated with neuropathic pain states, and reﬂex sympa-
thetic dystrophy or complex regional pain syndrome.
utilized by ﬁbromyalgia patients to treat its myriad
FIG. 3. Bar graph of change in migraine
frequency after cannabis treatment, adapted
from data from Rhyne et al.
Russo; Cannabis and Cannabinoid Research 2016, 1.1
symptoms. In an uncontrolled trial in nine patients,
THC was administered in doses of 2.5–15 mg a day for
Surprisingly, the ethics committee would
notpermitplacebouseinthestudy. Unfortunately, all
side effects, but those completing had marked reductions
in subjective pain visual analog scales (VAS) ( p<0.01)
(Fig. 4). No beneﬁts on touch-evoked allodynia, nor
pinprick hyperalgesia, were documented.
Another group examined nabilone, a semisynthetic
THC analog and CB
agonist of 10-fold higher poten-
Forty ﬁbromyalgia patients received nabilone
1 mg BID for 4 weeks. Visual analog scales of pain, a
Fibromyalgia Impact Questionnaire, and anxiety scores
were all statistically signiﬁcantly beneﬁted compared
with placebo ( p<0.02). The effects on sleep were also
assessed with nabilone
in 31 patients with doses of
0.5–1 mg at bedtime compared with patients taking
amitriptyline 10–20 mg. Nabilone was superior on an
Insomnia Severity Index, but no beneﬁts on pain, mea-
sure of mood, or quality of life were observed.
Herbal cannabis was utilized in an open-label man-
ner in 28 ﬁbromyalgia patients in comparison with
an equal number of matched control patients
another report. Two hours after cannabis use, VAS
scores showed a statistically signiﬁcant ( p<0.001) re-
duction of pain and stiffness, enhancement of relaxa-
tion, and an increase in somnolence and feeling of
well-being. The mental health component summary
score of the Short Form (36) Health Survey (SF-36)
was signiﬁcantly higher ( p<0.05) in cannabis users
than in nonusers.
Other cannabis-based medicine clinical trials have
been noteworthy in their beneﬁts on symptomatic
reduction allowing sleep (reviewed in Refs.
and the same would likely be obtained in ﬁbromyal-
gia, which displays many features in common with
other causes of peripheral neuropathic pain. A nota-
ble example would be adjunctive use of Sativex
(USAN: nabiximols) in a 5-week RCT in 125 patients
with intractable peripheral neuropathic pain with
allodynia in which it proved superior to placebo
(p=0.00) in Box Scale-11 (BS-11) score change and
reduced dynamic allodynia test scores versus placebo
While this degree of beneﬁt is yet to be shown in for-
mal RCTs in ﬁbromyalgia, the court of public opinion
supports its utility. A recent survey on efﬁcacy of three
regulatory body-approved pharmaceutical ﬁbromyal-
gia treatments versus cannabis recently garnered in ex-
cess of 1300 respondents and is available online from
the National Pain Report.
Of the approved drugs for ﬁbromyalgia, duloxetine
and milnacipran are mixed serotonin and adrenergic
uptake inhibitors, while pregabalin is an anticonvulsant
drug repurposed to treat neuropathic pain. Results of
the survey (Fig. 5) strongly favor cannabis over the
poorly effective prescription medicines. These results
certainly support an urgent need for more deﬁnitive
RCTs of a well-formulated and standardized cannabis-
based medicine in ﬁbromyalgia inasmuch as existing
current medicines with regulatory approval seem to
fall quite short of the mark.
Additional Conditions Suggesting CED
The ECS has been demonstrated to play a key role in
the pathophysiology of motion sickness
subjecting volunteers to parabolic ﬂight maneuvers
producing microgravity. Seven of 21 adults so tested
developed acute motion sickness with signiﬁcant re-
ductions in AEA ( p=0.04) and 2-AG ( p=0.01) in
blood. Nausea scores correlated negatively with AEA
(p=0.02), and even CB
receptor mRNA gene expres-
sion in leukocytes diminished signiﬁcantly ( p=0.03)
4 h after exposure in the most adversely affected.
Animal models have clearly established the role of the
ECS in multiple sclerosis (MS).
Direct assays of AEA
FIG. 4. Bar graph depicting decreases in pain in
the per-protocol subset of ﬁbromyalgia patients
taking THC, adapted from data from Schley
THC, tetrahydrocannabinol (dronabinol).
Russo; Cannabis and Cannabinoid Research 2016, 1.1
and 2-AG in the CSF of MS patients versus controls con-
ﬁrm signiﬁcant deﬁcits in affected patients, particularly
in secondary progressive cases, conﬁrming an impaired
and afﬁrming the value of
such measurements as a functional disease marker.
In a recent interesting ﬁnding assessing central pain
mechanisms in neuropathy due to diabetes, streptozoto-
cin was administered in a rat model that demonstrated
reduced rostroventromedial medullary AEA levels, and
in which the TRPV1 desensitizer, capsaicin, decreased
nociceptive behavioral signs,
as well as demonstrating
the central effects of a supposedly peripheral disorder. If
corroborated in human studies, this ﬁnding might add
diabetic neuropathy to the growing list of putative endo-
cannabinoid deﬁciency disorders.
In 2008, a mouse model of Huntington’s disease
(HD) demonstrated a widespread impairment of endo-
Subsequently, in the postmor-
tem brains of human patients with HD,
a striking loss
of immunoreactivity of CB
in putamen and globus
pallidus was demonstrated throughout the time course
of the disorder. The degree of change was much higher
than that for enkephalin or substance P, making CB
superior marker, even at earlier clinical stages. This loss
was felt to be a potential compensatory response
as it could reduce GABA release in the striatum. A sub-
sequent positron emission tomography (PET) study in
living HD sufferers,
employing 18F-MK9470, a CB
ligand, demonstrated signiﬁcant decreases in receptor
availability versus controls ( p<0.0001). These reduc-
tions ranged from 15% in cerebellum up to 25% in
frontal cortex, conﬁrming underactivity of the ECS in
HD that would disrupt neurotransmission and corre-
lated inversely with disease severity.
Direct laboratory measurements were also performed
in untreated Parkinson’s disease (PD) patients, examin-
and demonstrated a doubling of AEA levels
over age-matched controls ( p<0.001), irrespective of
disease stage. The authors posited this as a compensa-
tory mechanism in the striatum of PD patients in an
effort to alleviate dopamine depletion. Subsequently, an-
was the ﬁrst to demonstrate the role of the
ECS in synaptic long-term depression in motor circuits
in PD. The motor deﬁcits present in rodents with dopa-
mine lesions were reversed by combining a D2 agonist
with an endocannabinoid reuptake inhibitor. This ﬁnd-
ing suggests that progressive dopamine loss in PD in
striatal circuits may decrease endocannabinoid tone and
that the elevations in anandamide in PD patients may
be an attempt to compensate for this loss.
Prior animal research has elucidated the relationship
between the ECS, extinction of aversive memories,
This has been supplemented
by additional evidence that stress-induced anxiety is di-
rectly related to central anandamide deﬁciency in mice.
One genetic study in humans has linked genetic var-
iants of CNR1, the CB
receptor gene, to fear extinc-
Homozygote and heterozygote
G-allele carriers of the gene rs2180619 showed prom-
inent extinction of fear in a virtual reality experiment,
FIG. 5. Efﬁcacy of approved pharmaceuticals compared with cannabis in ﬁbromyalgia according to patient
survey results, adapted from data from National Pain Report.
Russo; Cannabis and Cannabinoid Research 2016, 1.1
while A/A homozygotes displayed an absence of fear-
potentiated startle reactions, conﬁrming the role of
the ECS in human fear extinction.
Recent research in humans has clariﬁed the role of
the ECS in post-traumatic stress. Forty-six survivors
of the World Trade Center attacks were studied.
Serum 2-AG was signiﬁcantly reduced in PTSD victims
versus those without PTSD symptoms, especially those
with direct exposure, suggesting a promotion of reten-
tion of aversive memories. A negative relationship was
also noted between AEA levels and intrusive symp-
toms. The authors indicated that research to date sug-
gests a good correlation of lower serum AEA levels to
receptor binding sites in CNS, as was
demonstrated in a PET study of untreated PTSD pa-
-selective radioligand [
on PET revealed higher volume of distribution (V
with lower AEA tone in PTSD ( p=0.001) by 19.5%
over healthy controls and 14.5% over traumatized
patients without PTSD. Cortisol levels were lower in
PTSD and trauma patients versus controls and OMAR
, AEA, and cortisol together correctly identiﬁed
85% of PTSD cases. Women had greater CB
availability under basal conditions, suggesting greater
susceptibility to development of PTSD, in accord
with epidemiological observations. Agents increasing
AEA availability were suggested as possible therapy
and such availability might reﬂect compensatory upre-
gulation as a reaction to reduced endocannabinoid lev-
els. Three excellent recent reviews reinforce these
The criticality of ECS function in other psychiatric
syndromes has been evidenced in studies of major de-
pression, which is now thought of less as a failure of
monoamine neurotransmission and more as a disorder
of CNS plasticity with an inﬂammatory component,
or even as a degenerative disease
directly linked to
endocannabinoid deﬁciency. Additionally, AEA levels
were eightfold higher in CSF of untreated acute schizo-
phrenics than in controls ( p=0.000), and AEA was
negatively correlated with psychotic symptoms ( p=
0.001), representing a compensatory mechanism to
Recent clinical trial work supports the
utility of cannabidiol in its treatment.
PET was also employed in a study of adult female
anorexia nervosa and bulimia patients,
ing that global CB
receptor availability was increased
in anorexia over controls in cortical and subcortical
areas ( p=0.0003), in the insula in both anorexia and
bulimia patients ( p=0.01 and p=0.004, respectively),
and in the inferior frontal and temporal areas in an-
orexia ( p=0.02). The authors related these chronic
upregulations of CB
activity to presumed ECS hypoac-
tivity (p. 780). Interestingly, peripheral serum AEA is
elevated in anorexia. Long ago, a single RCT was un-
dertaken in anorexia nervosa in 11 female patients
comparing THC to diazepam in a double-blind cross-
No increased weight gain was noted in
the THC group, but dosing was seemingly excessive
(up to 30 mg daily), as evidenced by paranoid ideation
and loss of control in three patients (27%). More recent
experience would suggest that lower THC dosing with
a cannabis-based preparation, as opposed to pure THC,
might yield different results with prospects for not only
fewer adverse events, but increased efﬁcacy as well.
Certainly, additional trials are warranted in this com-
mon and difﬁcult clinical context.
Given the current seemingly increased incidence and
recognition of autistic spectrum disorders, it is useful to
note their possible relationship with the ECS. Genes asso-
ciated with these disorders also regulate ECS function:
neuroligin-3 R451C-knockin and neuroligin-3 knockout
mutations in mice impaired tonic endocannabinoid
with the authors suggesting therapeutic ap-
proaches in the human afﬂiction to address this ﬁnding.
Similarly, presynaptic b-neurexins controlled synaptic
signals in excitatory synapses through regulation of post-
synaptic 2-AG production
and were said to be essential
for control of tonic endocannabinoid signaling.
Conclusions, Caveats, and Suggestions
for Additional Research on and Treatment of CED
The current review has examined the concept of CED
and presented more than a decade of supportive objec-
tive evidence. However, certain caveats are necessary.
One is that contradictory ﬁndings are not only possible
but also common. This is due, in part, to the often re-
ciprocal relationships between the two major endocan-
nabinoids, AEA and 2-AG, as expansively demonstrated
in a current review
: Anandamide is most often the
tonic signaling agent of the ECS and regulator of syn-
aptic transmission, while 2-arachidonoylglycerol acts
as a phasic signal activator in neuronal depolarization
and mediator of synaptic plasticity. Thus, discordant
levels of the two endocannabinoids may frequently be en-
countered. Additionally, while CED may be harmful,
excesses clearly are, as well, with obvious examples of
obesity, metabolic syndrome, and hepatic ﬁbrosis.
Aside from the evidence of depressed AEA levels in
the CSF of migraine sufferers
and the other examples
Russo; Cannabis and Cannabinoid Research 2016, 1.1
presented here, there has been little direct objective ev-
idence of the CED theory in patients until quite re-
cently. Additional investigations in a similar vein to
assess endocannabinoid levels in the serum or spinal
ﬂuid of migraine, IBS, and ﬁbromyalgia versus controls
would be illuminating. Anatomic and physiological
scanning techniques (e.g., fMRI, PET) are not yet capa-
ble of producing real-time direct assessments of endo-
cannabinoid levels in living patients, but hopefully
research will soon allow this type of screening assess-
ment in health and disease. Similarly, genomic testing
has produced great strides in elucidating the mutations
responsible for many congenital conditions, but has
not yet fully plumbed the depths of regulation of
gene function that may well underlie the putative
CED conditions discussed herein.
RCTs of CED conditions are certainly well justiﬁed
on the basis of current data and should replace the cur-
rent largely uncontrolled black market experiments
that desperate patients with these afﬂictions are con-
temporaneously forced to undertake in their quest for
relief of their symptoms.
Various strategies to treat CED conditions are possi-
ble. A direct approach with CB
agonists must recog-
nize the fact that the ECS operates as a homeostatic
regulator that sometimes requires a gentle pharmaco-
logical nudge, rather than a forceful shove, by synthetic
full agonists. Thus, small doses of a weak partial agonist
(e.g., THC) should be considered, which would not in-
duce tolerance and may jump-start the ECS. Even THC
alone is poorly tolerated or appreciated by patients,
and standardized whole cannabis extracts that contain
additional synergistic and buffering components, such
as CBD and cannabis terpenoids, are certainly prefera-
Alternatively, FAAH inhibitors will also raise AEA
levels, but only CBD among them has achieved current
legal commercial market availability. Pharmaceutical ap-
proaches affecting endocannabinoid transport or its ge-
netic regulation would also hold promise. Beyond drug
interventions, a growing body of knowledge supports
the realistic goal that lifestyle approaches should be in-
tegral to the treatment of CED; speciﬁcally, low-impact
aerobic regimens have demonstrated beneﬁcial ef-
fects on endocannabinoid function,
and as discussed
above, dietary manipulations with probiotics and
prebiotics may ameliorate not only IBS symptoms
but also the entire spectrum of CED conditions. Ulti-
mately, multimodality approaches are most likely to
be fruitful in treatment of these common yet difﬁcult
The assistance of Interlibrary Loan of Mansﬁeld Library,
University of Montana, is gratefully acknowledged.
Author Disclosure Statement
No competing ﬁnancial interests exist.
1. Russo EB. Hemp for headache: an in-depth historical and scientiﬁc review
of cannabis in migraine treatment. J Cannabis Ther. 2001;1:21–92.
2. Russo EB. Handbook of psychotropic herbs: a scientiﬁc analysis of herbal
remedies for psychiatric conditions. Haworth Press: Binghamton, NY,
3. Russo EB. Clinical endocannabinoid deﬁciency (CECD): can this con-
cept explain therapeutic beneﬁts of cannabis in migraine, ﬁbromyalgia,
irritable bowel syndrome and other treatment-resistant conditions?
Neuroendocrinol Lett. 2004;25:31–39.
4. McPartland JM, Guy GW, Di Marzo V. Care and feeding of the endocan-
nabinoid system: a systematic review of potential clinical interventions
that upregulate the endocannabinoid system. PLoS One. 2014;9:e89566.
5. Pacher P, Kunos G. Modulating the endocannabinoid system in human
health and disease—successes and failures. FEBS J. 2013;280:1918–1943.
6. Nicolodi M, Sicuteri F. Fibromyalgia and migraine, two faces of the same
mechanism. In: Recent Advances in Tryptophan Research (Filippini GA,
ed). Plenum Press: New York, 1996, pp. 373–379.
7. Peres MF, Young WB, Kaup AO, et al. Fibromyalgia is common in patients
with transformed migraine. Neurology. 2001;57:1326–1328.
8. Sperber AD, Atzmon Y, Neumann L, et al. Fibromyalgia in the irritable
bowel syndrome: studies of prevalence and clinical implications. Am J
9. Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake:
newborn suckling and appetite regulation in adulthood. Exp Biol Med
10. Fride E. Cannabinoids and cystic ﬁbrosis: a novel approach. J Cannabis
11. Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal ex-
tracts of cannabis for chronic pain: results from 34 ‘‘N of 1’’ studies.
12. Berman JS, Symonds C, Birch R. Efﬁcacy of two cannabis based medicinal
extracts for relief of central neuropathic pain from brachial plexus avul-
sion: results of a randomised controlled trial. Pain. 2004;112:299–306.
13. Jarvinen T, Pate D, Laine K. Cannabinoids in the treatment of glaucoma.
Pharmacol Ther. 2002;95:203–220.
14. Russo E. Cannabis treatments in obstetrics and gynecology: a historical
review. J Cannabis Ther. 2002;2:5–35.
15. Westfall R, Janssen P, Lucas P, et al. Survey of medicinal cannabis use
among childbearing women: patterns of its use in pregnancy and retro-
active self-assessment of tis efﬁcacy against ‘morning sickness’. Com-
plement Ther Clin Pract. 2006;12:27–33.
16. Marsicano G, Wotjak CT, Azad SC, et al. The endogenous cannabinoid sys-
tem controls extinction of aversive memories. Nature. 2002;418:530–534.
17. Hohmann AG, Suplita RL, Bolton NM, et al. An endocannabinoid mech-
anism for stress-induced analgesia. Nature. 2005;435:1108–1112.
18. Ashton CH, Moore PB, Gallagher P, et al. Cannabinoids in bipolar affec-
tive disorder: a review and discussion of their therapeutic potential.
J Psychopharmacol. 2005;19:293–300.
19. Clarke G, Cryan JF, Dinan TG, et al. Review article: probiotics for the
treatment of irritable bowel syndrome—focus on lactic acid bacteria.
Aliment Pharmacol Ther. 2012;35:403–413.
20. Holzer P. Gastrointestinal afferents as targets of novel drugs for the
treatment of functional bowel disorders and visceral pain. Eur J Phar-
21. Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut.
22. Di Carlo G, Izzo AA. Cannabinoids for gastrointestinal diseases: potential
therapeutic applications. Expert Opin Investig Drugs. 2003;12:39–49.
23. O’Shaughnessy WB. On the preparations of the Indian hemp, or gunjah
(Cannabis indica); their effects on the animal system in health, and their
Russo; Cannabis and Cannabinoid Research 2016, 1.1
utility in the treatment of tetanus and other convulsive diseases. Trans
Med Phys Soc Bengal. 1838–1840;71–102:421–461.
24. Izzo AA, Capasso F, Costagliola A, et al. An endogenous cannabinoid tone
attenuates cholera toxin-induced ﬂuid accumulation in mice. Gastroen-
25. Smid SD, Bjorklund CK, Svensson KM, et al. The endocannabinoids
anandamide and 2-arachidonoylglycerol inhibit cholinergic contractility
in the human colon. Eur J Pharmacol. 2007;575:168–176.
26. Akbar A, Yiangou Y, Facer P, et al. Increased capsaicin receptor TRPV1-
expressing sensory ﬁbres in irritable bowel syndrome and their correla-
tion with abdominal pain. Gut. 2008;57:923–929.
27. Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for canna-
bidiol and its synthetic analogues: effect on vanilloid VR1 receptors and
on the cellular uptake and enzymatic hydrolysis of anandamide. Br J
28. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances ananda-
mide signaling and alleviates psychotic symptoms of schizophrenia.
Transl Psychiatry. 2012;2:e94.
29. Wong BS, Camilleri M, Eckert D, et al. Randomized pharmacodynamic and
pharmacogenetic trial of dronabinol effects on colon transit in irritable
bowel syndrome-diarrhea. Neurogastroenterol Motil. 2012;24:358-e169.
30. Camilleri M, Kolar GJ, Vazquez-Roque MI, et al. Cannabinoid receptor 1
gene and irritable bowel syndrome: phenotype and quantitative traits.
Am J Physiol Gastrointest Liver Physiol. 2013;304:G553–G560.
31. Ware MA, Adams H, Guy GW. The medicinal use of cannabis in the UK:
results of a nationwide survey. Int J Clin Pract. 2005;59:291–295.
32. Esfandyari T, Camilleri M, Busciglio I, et al. Effects of a cannabinoid re-
ceptor agonist on colonic motor and sensory functions in humans: a
randomized, placebo-controlled study. Am J Physiol Gastrointest Liver
33. Klooker TK, Leliefeld KE, Van Den Wijngaard RM, et al. The cannabinoid
receptor agonist delta-9-tetrahydrocannabinol does not affect visceral
sensitivity to rectal distension in healthy volunteers and IBS patients.
Neurogastroenterol Motil. 2011;23:30–35, e2.
34. Rousseaux C, Thuru X, Gelot A, et al. Lactobacillus acidophilus modulates
intestinal pain and induces opioid and cannabinoid receptors. Nat Med.
35. Cluny NL, Keenan CM, Reimer RA, et al. Prevention of diet-induced obe-
sity effects on body weight and gut microbiota in mice treated chroni-
cally with delta9-tetrahydrocannabinol. PLoS One. 2015;10:e0144270.
36. Capasso R, Orlando P, Pagano E, et al. Palmitoylethanolamide normalizes
intestinal motility in a model of post-inﬂammatory accelerated transit:
involvement of CB(1) receptors and TRPV1 channels. Br J Pharmacol.
37. Underwood E. A shot at migraine. Science. 2016;351:116–119.
38. Russo E. Cannabis for migraine treatment: the once and future prescrip-
tion? An historical and scientiﬁc review. Pain. 1998;76:3–8.
39. Baron EP. Comprehensive review of medicinal marijuana, cannabinoids,
and therapeutic implications in medicine and headache: what a long
strange trip it’s been. Headache. 2015;55:885–916.
40. Greco R, Gasperi V, Maccarrone M, et al. The endocannabinoid system
and migraine. Exp Neurol. 2010;224:85–91.
41. Boger DL, Patterson JE, Jin Q. Structural requirements for 5-HT2A and
5-HT1A serotonin receptor potentiation by the biologically active lipid
oleamide. Proc Natl Acad Sci U S A. 1998;95:4102–4107.
42. Walker JM, Hohmann AG, Martin WJ, et al. The neurobiology of canna-
binoid analgesia. Life Sci. 1999;65:665–673.
43. Akerman S, Kaube H, Goadsby PJ. Anandamide is able to inhibit trigem-
inal neurons using an in vivo model of trigeminovascular-mediated
nociception. J Pharmacol Exp Ther. 2003;309:56–63.
44. Akerman S, Kaube H, Goadsby PJ. Anandamide acts as a vasodilator of
dural blood vessels in vivo by activating TRPV1 receptors. Br J Pharmacol.
45. Fusco BM, Barzoi G, Agro F. Repeated intranasal capsaicin applications to
treat chronic migraine. Br J Anaesth. 2003;90:812.
46. Akerman S, Holland PR, Goadsby PJ. Cannabinoid (CB1) receptor activa-
tion inhibits trigeminovascular neurons. J Pharmacol Exp Ther.
47. Greco R, Mangione AS, Sandrini G, et al. Effects of anandamide in mi-
graine: data from an animal model. J Headache Pain. 2011.
48. Cupini LM, Bari M, Battista N, et al. Abnormal degradation of endocan-
nabinoids in migrainous women. Cephalalgia. 2003;23:684.
49. Cupini LM, Costa C, Sarchielli P, et al. Degradation of endocannabinoids
in chronic migraine and medication overuse headache. Neurobiol Dis.
50. Rossi C, Pini LA, Cupini ML, et al. Endocannabinoids in platelets of chronic
migraine patients and medication-overuse headache patients: relation
with serotonin levels. Eur J Clin Pharmacol. 2008;64:1–8.
51. Sarchielli P, Pini LA, Coppola F, et al. Endocannabinoids in chronic mi-
graine: CSF ﬁndings suggest a system failure. Neuropsychopharmacol-
52. Kazemi H, Rahgozar M, Speckmann EJ, et al. Effect of cannabinoid
receptor activation on spreading depression. Iran J Basic Med Sci.
53. Perrotta A, Arce-Leal N, Tassorelli C, et al. Acute reduction of anandamide-
hydrolase (FAAH) activity is coupled with a reduction of nociceptive
pathways facilitation in medication-overuse headache subjects after
withdrawal treatment. Headache. 2012;52:1350–1361.
54. Nozaki C, Markert A, Zimmer A. Inhibition of FAAH reduces nitroglycerin-
induced migraine-like pain and trigeminal neuronal hyperactivity in mice.
Eur Neuropsychopharmacol. 2015;25:1388–1396.
55. Juhasz G, Lazary J, Chase D, et al. Variations in the cannabinoid receptor
1 gene predispose to migraine. Neurosci Lett. 2009;461:116–120.
56. el-Mallakh RS. Marijuana and migraine. Headache. 1987;27:442–443.
57. Rhyne DN, Anderson SL, Gedde M, et al. Effects of medical marijuana on
migraine headache frequency in an adult population. Pharmacotherapy.
58. Gowers WR. A lecture on lumbago: its lessons and analogues. Br Med J.
59. Caro XJ, Winter EF. The role and importance of small ﬁber neuropathy in
ﬁbromyalgia pain. Curr Pain Headache Rep. 2015;19:55.
60. Bennett RM. Rational management of ﬁbromyalgia. Rheum Dis Clin North
61. Bennett RM. The rational management of ﬁbromyalgia patients. Rheum
Dis Clin North Am. 2002;28:181–199, v.
62. Nicolodi M, Volpe AR, Sicuteri F. Fibromyalgia and headache. Failure
of serotonergic analgesia and N-methyl-D-aspartate-mediated neu-
ronal plasticity: their co mmon clues. Cephalalgia. 1998;18(Suppl 21):
63. Richardson JD, Aanonsen L, Hargreaves KM. Hypoactivity of the spinal
cannabinoid system results in NMDA-dependent hyperalgesia. J Neuro-
64. Schley M, Legler A, Skopp G, et al. Delta-9-THC based monotherapy in
ﬁbromyalgia patients on experimentally induced pain, axon reﬂex ﬂare,
and pain relief. Curr Med Res Opin. 2006;22:1269–1276.
65. Skrabek RQ, Galimova L, Ethans K, et al. Nabi lone for the treatment of pain
in ﬁbromyalgia. J Pain. 2008;9:164–173.
66. Ware MA, Fitzcharles MA, Joseph L, et al. The effects of nabilone on sleep
in ﬁbromyalgia: results of a randomized controlled trial. Anesth Analg.
67. Fiz J, Duran M, Capella D, et al. Cannabis use in patients with ﬁbromyalgia:
effect on symptoms relief and health-related quality of life. PLoS One.
68. Russo EB, Guy GW, Robson PJ. Cannabis, pain, and sleep: lessons from
therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem
69. Russo EB, Hohmann AG. Role of cannabinoids in pain management. In:
Comprehensive Treatment of Chronic Pain by Medical, Interventional and
Behavioral Approaches (Deer T, Gordin V, eds.). Springer: New York, 2013,
70. Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats
neuropathic pain characterised by allodynia: a randomised, double-blind,
placebo-controlled clinical trial. Pain. 2007;133:210–220.
71. National Pain Report. Marijuana rated most effective for treating ﬁbro-
myalgia. National Pain Report, 2014. Available at: http://nationalpainreport
72. Chouker A, Kaufmann I, Kreth S, et al. Motion sickness, stress and the
endocannabinoid system. PLoS One. 2010;5:e10752.
73. Baker D, Pryce G, Croxford JL, et al. Endocannabinoids control spasticity in
a multiple sclerosis model. FASEB J. 2001;15:300–302.
74. Di Filippo M, Pini LA, Pelliccioli GP, et al. Abnormalities in the cerebro-
spinal ﬂuid levels of endocannabinoids in multiple sclerosis. J Neurol
Neurosurg Psychiatry. 2008;79:1224–1229.
Russo; Cannabis and Cannabinoid Research 2016, 1.1
75. Silva M, Martins D, Charrua A, et al. Endovanilloid control of pain modu-
lation by the rostroventromedial medulla in an animal model of diabetic
neuropathy. Neuropharmacology. 2016;107:49–57.
76. Bisogno T, Martire A, Petrosino S, et al. Symptom-related changes of
endocannabinoid and palmitoylethanolamide levels in brain areas of
R6/2 mice, a transgenic model of Huntington’s disease. Neurochem Int.
77. Allen KL, Waldvogel HJ, Glass M, et al. Cannabinoid (CB(1)), GABA(A) and
GABA(B) receptor subunit changes in the globus pallidus in Huntington’s
disease. J Chem Neuroanat. 2009;37:266–281.
78. Van Laere K, Casteels C, Dhollander I, et al. Widespread decrease of type 1
cannabinoid receptor availability in Huntington disease in vivo. J Nucl
79. Pisani A, Fezza F, Galati S, et al. High endogenous cannabinoid levels in
the cerebrospinal ﬂuid of untreated Parkinson’s disease patients. Ann
80. Kreitzer AC, Malenka RC. Endocannabinoid-mediated rescue of striatal
LTD and motor deﬁcits in Parkinson’s disease models. Nature.
81. Bluett RJ, Gamble-George JC, Hermanson DJ, et al. Central anandamide
deﬁciency predicts stress-induced anxiety: behavioral reversal through
endocannabinoid augmentation. Transl Psychiatry. 2014;4:e408.
82. Heitland I, Klumpers F, Oosting RS, et al. Failure to extinguish fear and
genetic variability in the human cannabinoid receptor 1. Transl Psychia-
83. Hill MN, Bierer LM, Makotkine I, et al. Reductions in circulating endo-
cannabinoid levels in individuals with post-traumatic stress disorder fol-
lowing exposure to the World Trade Center attacks.
84. Neumeister A, Normandin MD, Pietrzak RH, et al. Elevated brain can-
nabinoid CB1 receptor avai lability in post-traumatic stress diso rder:
a positron emission tomography study. Mol Psychiatry. 2013;18:
85. Neumeister A, Seidel J, Ragen BJ, et al. Translational evidence for a role of
endocannabinoids in the etiology and treatment of posttraumatic stress
disorder. Psychoneuroendocrinology. 2015;51:577–584.
86. Gabbay FE, Choi KH, Wynn GH, et al. The role of endoncannbinoid function
in posttraumatic stress disorder: modulation the risk phenotype and ren-
dering effects of trauma. In: Cannabinoids in Neurologic and Mental Dis-
ease (Fattore L, ed.). Academic Press: London, 2015, pp. 247–288.
87. Morena M, Patel S, Bains JS, et al. Neurobiological interactions between
stress and the endocannabinoid system. Neuropsychopharmacology.
88. Hill MN, Gorzalka BB. Is there a role for the endocannabinoid system in
the etiology and treatment of melancholic depression? Behav Pharmacol.
89. Giuffrida A, Leweke FM, Gerth CW, et al. Cerebrospinal anandamide levels
are elevated in acute schizophrenia and are inversely correlated with
psychotic symptoms. Neuropsychopharmacology. 2004;29:2108–2114.
90. Gerard N, Pieters G, Gofﬁn K, et al. Brain type 1 cannabinoid receptor
availability in patients with anorexia and bulimia nervosa. Biol Psychiatry.
91. Gross H, Ebert MH, Faden VB, et al. A double-blind trial of delta 9-
tetrahydrocannabinol in primary anorexia nervosa. J Clin Psychophar-
92. Portenoy RK, Ganae-Motan ED, Allende S, et al. Nabiximols for opioid-
treated cancer patients with poorly-controlled chronic pain: a random-
ized, placebo-controlled, graded-dose trial. J Pain. 2012;13:438–449.
93. Russo EB. Taming THC: potential cannabis synergy and
phytocannabinoid-terpenoid entourage effects. Br J Pharmacol.
94. Russo EB, Mead AP, Sulak D. Current status and future of cannabis re-
search. Clin Researcher. 2015:58–63.
95. Foldy C, Malenka RC, Sudhof TC. Autism-associated neuroligin-3 muta-
tions commonly disrupt tonic endocannabinoid signaling. Neuron.
96. Anderson GR, Aoto J, Tabuchi K, et al. Beta-neurexins control neural cir-
cuits by regulating synaptic endocannabinoid signaling. Cell.
97. Pacher P, Kunos G. Cardiovascular, metabolic, liver kidney and inﬂam-
matory disorders. In: Handbook of Cannabis (Pertwee R, ed.). Oxford
University Press: Oxford, United Kingdom, 2014, pp. 564–581.
98. Calhoun SR, Galloway GP, Smith DE. Abuse potential of dronabinol
(Marinol). J Psychoactive Drugs. 1998;30:187–196.
induced endocannabinoid signaling in humans and cursorial mammals
with implications for the ‘runner’s high’. J Exp Biol. 2012;215:1331–
Cite this article as: Russo EB (2016) Clinical endocannabinoid deﬁ-
ciency reconsidered: current research supports the theory in mi-
graine, ﬁbromyalgia, irritable bowel and other treatment-resistant
syndromes, Cannabis and Cannabinoid Research 1:1, 154–165, DOI:
5-HT ¼5-hydroxytryptamine (serotonin)
AEA ¼arachidonylethanolamide (anandamide)
BS-11 ¼Box Scale-11
¼cannabinoid receptor 1 or 2
CED ¼clinical endocannabinoid deﬁciency
CGRP ¼calcitonin gene-related peptide
CM ¼chronic migraine
CNS ¼central nervous system
CSF ¼cerebrospinal ﬂuid
ECS ¼endocannabinoid system
FAAH ¼fatty acid amide hydrolase
fMRI ¼functional magnetic resonance imaging
GABA ¼gamma-aminobutyric acid
HD ¼Huntington’s disease
IBS ¼irritable bowel syndrome
IBS-D ¼irritable bowel syndrome with diarrhea
MS ¼multiple sclerosis
NO ¼nitric oxide
PD ¼Parkinson’s disease
PET ¼positron emission tomography
PTSD ¼post-traumatic stress disorder
RCT ¼randomized controlled trial
SF-36 ¼Short Form (36) Health Survey
THC ¼tetrahydrocannabinol (dronabinol)
TRPV ¼transient receptor potential vanilloid receptor
VAS ¼visual analog scale
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