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Cannabidiol (CBD) as a treatment of acute and chronic back pain: A case series and literature review

May 2020
Journal of Opioid Management 16(3):215-218

DOI:10.5055/jom.2020.0570

Authors:

Objective: Two patient case reports are presented describing the use of cannabidiol (CBD) for the symptomatic relief of a lumbar compression fracture and in the mitigation of thoracic discomfort and dysesthesia secondary to a surgically resected meningioma. Discussion: CBD appears to have antisnociceptive and anti-inflammatory effects on opioid-naive patients with neuro-pathic and radicular pain. Of note, the patients in this case series used the same CBD cream: Baskin Essentials Body Wellness Cream (400 mg CBD per two oz.) Conclusion: Hemp-derived CBD in a transdermal cream provided significant symptom and pain relief for the patients described in this case series. Based on these results, we believe further investigation is warranted to see if CBD-containing products should have a more prominent role in the treatment of acute and chronic pain.

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215

Journal of Opioid Management 16:3 n May/June 2020

CliniCal RepoRt

Cannabidiol (CBD) as a treatment of acute and chronic back pain:

A case series and literature review

Jonathan P. Eskander, MD, MBA; Junaid Spall, BS; Awais Spall, BA;

Rinoo V. Shah, MD, MBA; Alan D. Kaye, MD, PhD

ABSTRACT

Objective: Two patient case reports are presented describing the use of canna-

bidiol (CBD) for the symptomatic relief of a lumbar compression fracture and in

the mitigation of thoracic discomfort and dysesthesia secondary to a surgically

resected meningioma.

Discussion: CBD appears to have antisnociceptive and anti-inflammatory

effects on opioid-naive patients with neuropathic and radicular pain. Of note,

the patients in this case series used the same CBD cream: Baskin Essentials Body

Wellness Cream (400 mg CBD per two oz.)

Conclusion: Hemp-derived CBD in a transdermal cream provided significant

symptom and pain relief for the patients described in this case series. Based on

these results, we believe further investigation is warranted to see if CBD-containing

products should have a more prominent role in the treatment of acute and chronic

pain.

INTRODUCTION

Cannabidiol (CBD) is a phytocannabinoid and

one of the most abundant 113 identified cannabi-

noids as well as 432 other chemical compounds

found in the cannabis plant.1,2 Its mechanism

of action has not been determined; however, it

may interact with numerous targets. However,

the Food and Drug Administration (FDA) has

approved the CBD drug Epidiolex® for the treat-

ment of two forms of rare childhood epilepsy

disorders: Dravet syndrome and Lennox-Gastaut

syndrome.3 Based on previous research, cannabi-

noids seem to possess antinociceptive responses

stemming from nociceptive neuron inhibition and

pain processing.2

Cannabinoid (CB) receptors decrease excita-

tory neurotransmission, modulate psychotrophic

effects, as well as ventral tegmental dopamine neu-

ronal activity critically associated with addiction.2

Cannabinoids exert their effects via the activation of

the G-protein coupled receptors, cannabinoid CB1

and CB2. Additionally, it is possible that there are still

more cannabinoid receptors still unknown to us. CB1

receptors are found predominantly along the pain

pathways of the central nervous system4 as well as in

the ocular, cardiovascular, and gastrointestinal sys-

tems.5 The CB2 receptor, which has a significantly

lower affinity for THC compared to CB1,5 is found

primarily in the immune system.6-8 Some authors sug-

gest that CB1 and CB2 agonists might induce antino-

ciception via the release of endogenous opioids and

Keywords:

cannabidiol

CBD

compression fracture

low back pain

chronic pain

neuropathic

radicular

pain

marijuana

THC

tetrahydrocannabinol

CB1

CB2

receptors

meningioma

dysesthesia

parasthesia

thoracic back pain

ARTICLE INFO

DOI:10.5055/jom.2020.0570

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Journal of Opioid Management 16:3 n May/June 2020

216

possibly by increasing opioid precursor gene expres-

sion.8 Emerging research suggests that cannabi-

noids may be promising treatments for neuropathic,

inflammatory, and oncologic pain.8

Endocannabinoids, a family of bioactive lipids,

are derived from arachidonic acid metabolism. They

are structurally like arachidonic acid and chemi-

cals that interact with the endocannabinoid system

are believed to diminish inflammation. Arachidonic

acid metabolite regulation is also part of the mech-

anism by which nonsteroidal anti-inflammatory

drugs (NSAIDs) reduce pain and inflammation. This

includes cyclooxygenase-2 (COX-2) inhibition and

fatty acid amide hydrolase (FAAH). Regulation of

these pathways leads to increased endocannabinoids

anandamide (AEA), as well as decreased arachidonic

acid and prostaglandin levels. Endocannabinoid

production is also increased by the conversion of

omega-3 fatty acids which possess anti-inflamma-

tory and vasodilatory properties.9,10 It is believed

that endocannabinoids activate previously described

cannabinoid receptors and modulate neural trans-

mission.8 This suggests that endocannabinoids par-

ticipate in a variety of cerebral and systemic functions

including pain perception, mood-enhancement, anti-

inflammatory effects, and more.11

Encouraging results in the treatment of chronic

pain in animal models have recently been demon-

strated by compounds with multiple mechanisms.12

CBD treatment in diabetic mice showed a reduc-

tion in tactile allodynia, which suggests an effect

on neuropathic pain. Additionally, CBD has shown

antinociceptive and anti-inflammatory properties

without known adverse effects to the central nerv-

ous system.11,13

Regarding neuropathic pain, CB1 agonists work

alongside a set of receptors known as transient

receptor potentials (TRPs). TRPs refers to groups

of ion channels located across plasma membranes

of various organ systems and nerve cells. These ion

channels have nonselective permeability for cati-

ons, the regulation of which, can alter inflammatory

responses.14 As Lowin and Straub note, TRPs induce

the sensation of pain but also support inflamma-

tion via secretion of pro-inflammatory cytokines.14

An important subgroup within this receptor super-

family includes the TRP Vanilloid receptors, which

have been studied to bind to various cannabi-

noids.15 Upon activation, via entrance of calcium

and magnesium, the TRPV1 channel undergoes

desensitization, which has a considerable impact on

nerve-affiliated nociceptive transduction.16 These

hyperalgesic effects of TRPs are critical for under-

standing the physiological dynamics of chronic

nerve injury and pain. Furthermore, nerve injury

also triggers an immunological response initiating

the production of inflammatory macrophages that

retract sympathetic nerve fibers.14 Hypothalamic

norepinephrine thus falls under the threshold for

anti-inflammatory beta-2 receptor activation and this

favors pro-inflammatory effects, via alpha-adrener-

gic signaling.17 Further down in the cascade, this can

lead to an increase of nerve fiber signaling to the

CNS that triggers nociception. In chronic inflamma-

tory conditions, pro-inflammatory cytokines, such

as TNF and IL-10, can over-sensitize TRPV1 recep-

tors.18 Inhibiting TRPV1 function via CB1 activation

and FAAH inhibition reduces intracellular calcium

that can initiate analgesia by reducing the inflamma-

tory cytokine cascade often associated with pain.19

The immunomodulatory component of cannabi-

noids is indirectly accompanied by the antihyper-

algesic effects initiated by the ionotropic regulation

of Ca+.

The route of administration of CBD in the two

patients discussed in this report is transdermal.

Previous studies, using animal models, describe the

steady-state plasma concentrations of transdermal

CBD in guinea pigs did reach potentially therapeu-

tic levels (6.3 ng/mL) which was reached 15 hours

after application. Enhancers did increase absorption

3.7-fold.20 Of note, some CBD creams for sale use

proprietary technology to enhance the absorption

of CBD via the transdermal route. Another study

involved mice and transdermal ethosome CBD.

After application, CBD levels lasted at least 72 hours

and notably there was significant accumulation of

CBD as measured in underlying muscle.21

Some potential side effects of cannabinoids

include increased bleeding risk via suppression of

platelets and anticoagulants.22 In addition, CBD can

interact with warfarin and increase the risk of bleed-

ing complications. Like warfarin, CBD is metabo-

lized through the hepatic P450 enzyme system.

Both share the same isoforms in their metabolism.

CBD acts on CYP1A1, CYP1A2, CYP2C9, CYP2C19,

CYP2D6, CYP3A4, and CYP3A5.

CASE 1

A 40-year-old African American man pre-

sented with 8/10 low back pain secondary to an

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217

Journal of Opioid Management 16:3 n May/June 2020

L3 compression fracture suffered after a fall. His

medical history is significant for an epidural abscess

requiring evacuation and subsequent posterior

instrumentation and fusion of the lumbar spine

10 years ago. He does not take any medications.

After it was determined by his healthcare provid-

ers that he was not a candidate for a kyphoplasty,

he began conservative therapy using a combination

of acetamenophen and NSAIDS; neither of which

provided significant relief. Beginning on week two

status-post L3 vertebral compression fracture, he

began applying CBD cream twice daily to his lower

back. He applied a small amount of cream over the

affected area. He endorsed approximately 10 hours

of pain reduction to a 1/10 or 2/10. Pain from low

back muscle spasms as well as radiating pain to his

sacrum were mitigated. After 4 weeks of treatment,

he stopped using all medications as his low back

pain resolved.

CASE 2

A 61-year-old Caucasian woman presenting with

thoracic sensory disturbance and dysesthesia for

over 2 years following a surgical resection of a spi-

nal meningioma at the T6-7 level involving the lat-

eral intradural extramedullary compartment of the

vertebral canal. Her medical history is significant for

rheumatoid arthritis, cervical degenerative disc dis-

ease with left-sided radiculopathy, and obesity. Her

medications include methotrexate and simvastatin.

After using CBD cream applied to the affected area

of her thoracic spine, she endorsed approximately

7-8 hours of relief from sensory disturbance and

dysesthesia.

DISCUSSION AND CONCLUSION

The CBD has multiple theoretical targets includ-

ing CB2 receptors, alpha-2 adrenergic receptor ago-

nism, indirect stimulation of opioid receptors, and

mediators of the inflammatory processes and noci-

ceptive pathways. Modulation of the noradrenergic

system and indirect stimulation of opioid receptors

via CB2 receptors can be important in the treat-

ment of pain, anxiety, depression, and opioid with-

drawal. This could help explain why CBD appears

to be an effective antinociceptive compound. This

case series suggests that CBD may have antinocicep-

tive and anti-inflammatory effects on opioid-naive

patients with neuropathic and radicular pain. Due

to lack of evidence, it is unknown which products

containing CBD have a similar effect. Since CBD

creams are not regulated by the Food and Drug

Administration (FDA) it is difficult to determine the

efficacy and potency of each product in the market.

Interestingly, both of the aforementioned patients

used the same CBD cream: Baskin Essentials Body

Wellness Cream. Hemp-derived CBD in a topical

cream provided significant symptom and pain relief

for the patients described in this case series. It should

be noted that these products are third-party labora-

tory tested to ensure that the active ingredients are

as stated on the label. Based on these results, we

believe further investigation is warranted to see if

these products have a role in the treatment of acute

and chronic pain. A high-powered study involving

patients afflicted by either chronic and acute pain

conditions is warranted in order to examine to what

extent CBD can mitigate pain.

ACkNOwLEDgmENT

No funding was received for this manuscript.

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Jonathan P. Eskander, MD, MBA, Department of

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Junaid Spall, BS, Department of Chemistry, University of

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May 2020

Jonathan P Eskander

The purpose of this letter is to highlight three cases: 1) A 74-year-old male cadaveric kidney transplant recipient with a history of autosomal dominant polycystic kidney disease. His medical history is significant for multiple co-morbidities including chronic refractory gout, diabetes mellitus type 2, hypertension, dyslipidemia and coronary artery disease. After taking two grams of icosapent ethyl daily for six months, he demonstrated an attenuation of gout flares, reduction in Hemoglobin A1c (HbA1c), lower creatinine, lower C-Reactive Protein (CRP), endorsement of more energy with increased exercise tolerance, improved mood and less pain. Also of note, he stated that he has not had the common cold; which, for him is an unusually long period of time. During this time, he was able to wean his daily dosing of colchicine for gout. Due to an allopurinol allergy, he has been taking colchicine daily for gout prophylaxis over the past decade. 2) A 34-year-old Caucasian woman chronic fatigue syndrome and an elevated CRP for approximately 10 years. After initiating EPA therapy with 2 grams of icosapent ethyl daily for one month, she endorsed better energy and mood as well as more restful sleep. Her CRP levels also declined. 3) A 59-year-old Caucasian woman with a suspected COVID-19 infection status post antibiotic therapy with azithromycin developed a lingering productive cough persisting for approximately 3 weeks. After taking 2 grams of icosapent ethyl daily her symptoms resolved in 3 days. Since publication of the REDUCE-IT results in 2018, icosapent ethyl has demonstrated considerable cardiovascular risk reduction [1]; however, clinical evidence suggests there may be many more benefits that need to be investigated further. Some authors suggest that a high omega-6/ omega-3 ratio high-fat diet significantly contribute to metabolic disease states [2]. These diseases are numerous and include diabetes, atherosclerosis, obesity, gout and many other diseases of inflammation. The addition of icosapent ethyl is to help lower a person'somega-6/omega-3 ratio and contribute to improvement of diseases such as gout via mechanisms that are not entirely understood [3]. Currently, Eicosapentaenoic Acid (EPA) is believed to exert anti-inflammatory, virucidal [4], anti-cancer properties, reduce oxidative stress, and stabilize the cell lipid bilayer among other things. Interestingly, purified EPA may exert beneficial effects for patients with upper respiratory symptoms of viral infections; in the aforementioned case, a suspected COVID-19 infection. It is possible that EPA could blunt the cytokine release caused by COVID-19 as well as stabilize cell membranes, including the endothelium, against direct damage caused by the virus as well as counteract potential coagulopathies. Future studies with icosapent ethyl as an adjunct therapy are warranted across a wide range of disease states including metabolic diseases, autoimmune diseases, inflammation, dementia, proteopathies, mood disorders, viral infections, and certain cancers. References 1. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. 2. Xiao Y, Li X, Zeng X, Wang H, Mai Q, Cheng Y, et al. A low ω-6/ω-3 ratio high-fat diet improves rat metabolism via purine and tryptophan metabolism in intestine tract while reversed by inulin. J Agric Food Chem. 2019;67(26):7315-24.

Cannabis sativa L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer

Article

Full-text available

Dec 2018
BMRI

In the last decades, a lot of attention has been paid to the compounds present in medicinal Cannabis sativa L., such as Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain. The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety. Several studies have described CBD as a multitarget molecule, acting as an adaptogen, and as a modulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB 1 and CB 2 . CBD is present in both medicinal and fibre-type C. sativa plants, but, unlike Δ ⁹ -THC, it is completely nonpsychoactive. Fibre-type C. sativa (hemp) differs from medicinal C. sativa , since it contains only few levels of Δ ⁹ -THC and high levels of CBD and related nonpsychoactive compounds. In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggesting CBD (and CBD-like molecules present in the hemp extract) as a possible candidate for future clinical trials. CBD has been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ ⁹ -THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models. These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity. In the light of all these findings, in this review we explore the effects and the molecular mechanisms of CBD on inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ ⁹ -THC deprived hemp.

Medical Marijuana: Current Concepts, Pharmacological Actions of Cannabinoid Receptor Mediated Activation, and Societal Implications

Article

Full-text available

Jan 2018
Curr Pain Headache Rep

Purpose of review: The purpose of the following review is to summarize the history and current policies related to marijuana use and prevalence, basic and clinical science pharmacological literature regarding efficacy, subpopulations of concern, and varying policies regarding its use at present. Recent findings: With the increasingly widespread utilization of marijuana, there is also a growing complexity of public health policy, regulation, and necessity to further assess the medical indications and adverse long-term effects of marijuana use. Health care providers as well as the general public must be prepared to become familiar and up-to-date with medical literature, legislation, and educational material regarding medical marijuana.

Anti-inflammatory ω-3 endocannabinoid epoxides

Article

Full-text available

Jul 2017

Significance The health benefits of ω-3 fatty acids are mediated, in part, through metabolic conversion to bioactive epoxides. Here we detail the discovery and initial characterization of naturally occurring ω-3–derived endocannabinoid epoxides that are formed via enzymatic oxidation of ω-3 endocannabinoids by cytochrome P450s. These dual functional ω-3 endocannabinoid epoxides are anti-inflammatory and vasodilatory and reciprocally modulate platelet aggregation. By virtue of their physiological properties, they are expected to play important roles in neuroinflammation and in cerebrovascular diseases such as stroke.

Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis

Article

Full-text available

Sep 2015
ARTHRITIS RES THER

Chronic inflammation in rheumatoid arthritis (RA) is accompanied by activation of the sympathetic nervous system, which can support the immune system to perpetuate inflammation. Several animal models of arthritis already demonstrated a profound influence of adrenergic signaling on the course of RA. Peripheral norepinephrine release from sympathetic terminals is controlled by cannabinoid receptor type 1 (CB1), which is activated by two major endocannabinoids (ECs), arachidonylethanolamine (anandamide) and 2-arachidonylglycerol. These ECs also modulate function of transient receptor potential channels (TRPs) located on sensory nerve fibers, which are abundant in arthritic synovial tissue. TRPs not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides. In addition, many cell types in synovial tissue express CB1 and TRPs. In this review, we focus on CB1 and transient receptor potential vanilloid 1 (TRPV1)-mediated effects on RA since most anti-inflammatory mechanisms induced by cannabinoids are attributed to cannabinoid receptor type 2 (CB2) activation. We demonstrate how CB1 agonism or antagonism can modulate arthritic disease. The concept of functional antagonism with continuous CB1 activation is discussed. Since fatty acid amide hydrolase (FAAH) is a major EC-degrading enzyme, the therapeutic possibility of FAAH inhibition is studied. Finally, the therapeutic potential of ECs is examined since they interact with cannabinoid receptors and TRPs but do not produce central side effects.

Clinical and Pre-Clinical Evidence for Functional Interactions of Cannabidiol and Δ(9)-Tetrahydrocannabinol

Article

Sep 2017
NEUROPSYCHOPHARMACOL

The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are over 550 chemical compounds and over 100 phytocannabinoids isolated from cannabis, including Δ(9)-tetrahydrocannabinol (THC) and Cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC induced anxiety, psychosis and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from pre-clinical and human studies particularly with reference to anxiety and psychosis like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings including the individual and interactive effects of CBD and THC.Neuropsychopharmacology accepted article preview online, 06 September 2017. doi:10.1038/npp.2017.209.

Cannabinoids: Medical implications

Article

Feb 2016
ANN MED

Herbal cannabis has been used for thousands of years for medical purposes. With elucidation of the chemical structures of tetrahydrocannabinol (THC) and cannabidiol (CBD) and with discovery of the human endocannabinoid system, the medical usefulness of cannabinoids has been more intensively explored. While more randomized clinical trials are needed for some medical conditions, other medical disorders, like chronic cancer and neuropathic pain and certain symptoms of multiple sclerosis, have substantial evidence supporting cannabinoid efficacy. While herbal cannabis has not met rigorous FDA standards for medical approval, specific well-characterized cannabinoids have met those standards. Where medical cannabis is legal, patients typically see a physician who "certifies" that a benefit may result. Physicians must consider important patient selection criteria such as failure of standard medical treatment for a debilitating medical disorder. Medical cannabis patients must be informed about potential adverse effects, such as acute impairment of memory, coordination and judgment, and possible chronic effects, such as cannabis use disorder, cognitive impairment, and chronic bronchitis. In addition, social dysfunction may result at work/school, and there is increased possibility of motor vehicle accidents. Novel ways to manipulate the endocannbinoid system are being explored to maximize benefits of cannabinoid therapy and lessen possible harmful effects.

Medical cannabis: considerations for the anesthesiologist and pain physician

Article

Feb 2016

Purpose: New regulations are in place at the federal and provincial levels in Canada regarding the way medical cannabis is to be controlled. We present them together with guidance for the safe use of medical cannabis and recent clinical trials on cannabis and pain. Source: The new Canadian regulations on the use of medical cannabis, the provincial regulations, and the various cannabis products available from the Canadian Licensed Producers were reviewed from Health Canada, provincial licensing authorities, and the licensed producers website, respectively. Recent clinical trials on cannabis and pain were reviewed from the existing literature. Principal findings: Health Canada has approved a new regulation on medical marijuana/cannabis, the Marihuana for Medical Purposes Regulations: The production of medical cannabis by individuals is illegal. Health Canada, however, has licensed authorized producers across the country, limiting the production to specific licenses of certain cannabis products. There are currently 26 authorized licensed producers from seven Canadian provinces offering more than 200 strains of marijuana. We provide guidance for the safe use of medical cannabis. The recent literature indicates that currently available cannabinoids are modestly effective analgesics that provide a safe, reasonable therapeutic option for managing chronic non-cancer-related pain. Conclusion: The science of medical cannabis and the need for education of healthcare professionals and patients require continued effort. Although cannabinoids work to decrease pain, there is still a need to confirm these beneficial effects clinically and to exploit them with acceptable benefit-to-risk ratios.

Calcium entry via TRPV1 but not ASICs induces neuropeptide release from sensory neurons

Article

Apr 2014
MOL CELL NEUROSCI

Cyclooxygenase-2 Mediates Anandamide Metabolism in the Mouse Brain

Article

Nov 2010
J PHARMACOL EXP THER

Cyclooxygenase-2 (COX-2) mediates inflammation and contributes to neurodegeneration. Best known for its pathological up-regulation, COX-2 is also constitutively expressed within the brain and mediates synaptic transmission through prostaglandin synthesis. Along with arachidonic acid, COX-2 oxygenates the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol in vitro. Inhibition of COX-2 enhances retrograde signaling in the hippocampus, suggesting COX-2 mediates endocannabinoid tone in healthy brain. The degree to which COX-2 may regulate endocannabinoid metabolism in vivo is currently unclear. Therefore, we explored the effect of COX-2 inhibition on [(3)H]AEA metabolism in mouse brain. Although AEA is hydrolyzed primarily by fatty acid amide hydrolase (FAAH), ex vivo autoradiography revealed that COX-2 inhibition by nimesulide redirected [(3)H]AEA substrate from COX-2 to FAAH in the cortex, hippocampus, thalamus, and periaqueductal gray. These data indicate that COX-2 possesses the capacity to metabolize AEA in vivo and can compete with FAAH for AEA in several brain regions. Temporal fluctuations in COX-2 expression were observed in the brain, with an increase in COX-2 protein and mRNA in the hippocampus at midnight compared with noon. COX-2 immunolocalization was robust in the hippocampus and several cortical regions. Although most regions exhibited no temporal changes in COX-2 immunolocalization, increased numbers of immunoreactive cells were detected at midnight in layers II and III of the somatosensory and visual cortices. These temporal variations in COX-2 distribution reduced the enzyme's contribution toward [(3)H]AEA metabolism in the somatosensory cortex at midnight. Taken together, our findings establish COX-2 as a mediator of regional AEA metabolism in mouse brain.