~ Cannabis Anti-inflammation ~ Properties: Clinical Studies

Overview
Anti-inflammatory or antiinflammatory refers to the property of a substance or treatment that reduces inflammation or swelling.Professor at Hebrew University in Jerusalem, Dr. Mechoulam describes the role of Cannabinoids as anti-inflammatory for arthritis, as neuroprotectant for brain injury and as a possible treatment for PTSD. Dr. Mechoulam first isolated THC in 1964.

​Science & Research
Professor at Hebrew University in Jerusalem, Dr. Mechoulam describes the role of Cannabinoids as anti-inflammatory for arthritis, as neuroprotectant for brain injury and as a possible treatment for PTSD. Dr. Mechoulam first isolated THC in 1964.
Endocannabinoid System in Neuroprotection by Raphael Mechoulam,PhD 2014 - Study ~ The endocannabinoid system: an emerging key player in inflammation.

Clinical Studies

2014 - Study ~ Trans-Caryophyllene Suppresses Hypoxia-Induced Neuroinflammatory Responses by Inhibiting NF-κB Activation in Microglia.
2014 - Study ~ Endocannabinoids affect innate immunity of Muller glia during HIV-1 Tat cytotoxicity.
2014 - News ~ Drugs Related to Cannabis Have Pain-Relieving Potential for Osteoarthritis2013 - Study ~ Molecular evidence for the involvement of PPAR-δ and PPAR-γ in anti-inflammatory and neuroprotective activities of palmitoylethanolamide after spinal cord trauma
2013 - Study ~ The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties.
2013 - Study ~ Monoacylglycerol Lipase (MAGL) Inhibition Attenuates Acute Lung Injury in Mice.
2013 - Study ~ The monoacylglycerol lipase inhibitor JZL184 suppresses inflammatory pain in the mouse carrageenan model.
2013 - Study ~ The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain
2013 - Study ~ The Dual Effect of Cannabinoid Receptor-1 Deficiency on the Murine Postoperative Ileus
2013 - Study ~ Effects on Immune Cells of a New 1,8-Naphthyridin-2-One Derivative and Its Analogues as Selective CB2 Agonists: Implications in Multiple Sclerosis
2013 - Study ~ Glia and Mast Cells as Targets for Palmitoylethanolamide, an Anti-inflammatory and Neuroprotective Lipid Mediator.
2013 - Study ~ Cannabinoid receptor modulation of the endothelial cell inflammatory response
2013 - Study ~ Cannabinoid CB2 receptors as novel target for inhibiting house dust mite induced allergic airway inflammation
2013 - Study ~ Palmitoylethanolamide is a New Possible Pharmacological Treatment for the Inflammation Associated with Trauma
2013 - Study ~ Amyotrophic Lateral Sclerosis Treatment with Ultramicronized Palmitoylethanolamide
2013 - Study ~ Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: A role for A2A receptors.
2013 - Study ~ Controlling 2-arachidonoylglycerol metabolism as an anti-inflammatory strategy.
2013 - Study ~ Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors
2013 - Study ~ Prospects for cannabinoid therapies in viral encephalitis.
2013 - Study ~ Selective Activation of Cannabinoid Receptor 2 in Leukocytes Suppresses Their Engagement of the Brain Endothelium and Protects the Blood-Brain Barrier.
2013 - Study ~ The Influence of Cannabinoids on Generic Traits of Neurodegeneration.
2013 - Study ~ Cannabidiol in inflammatory bowel diseases: a brief overview.
2013 - Study ~ Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors.
2013 - Study ~ Long-term supplementation of honokiol and magnolol ameliorates body fat accumulation, insulin resistance, and adipose inflammation in high-fat fed mice.
2013 - Study ~ Magnolol inhibits LPS-induced inflammatory response in uterine epithelial cells : magnolol inhibits LPS-induced inflammatory response.
2013 - Study ~ Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract
2013 - Study ~ Anti-inflammatory effects of Cannabinoid 2 Receptor activation in endotoxin-induced uveitis.
2013 - Study ~ The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis.
2013 - Study ~ Endocannabinoids: a unique opportunity to develop multitarget analgesics.
2013 - Study ~ Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine inflammatory pain model.
2013 - News ~ Sending multiple sclerosis up in smoke
2013 - News ~ 5 Health Benefits Of Cannabichromene (CBC)
2013 - News ~ New Study: THC May Treat Inflammatory Diseases and Cancer By Altering Genes
2013 - News ~ Marijuana's Memory Paradox2012 - Study ~ Prolonged oral Cannabinoid Administration prevents Neuroinflammation, lowers beta-amyloid Levels and improves Cognitive Performance in Tg APP 2576 Mice.
2012 - Study ~ Mechanistic and Pharmacological Characterization of PF-04457845: A Highly Potent and Selective Fatty Acid Amide Hydrolase Inhibitor That Reduces Inflammatory and Noninflammatory Pain.
2012 - Study ~ The synthetic cannabinoid R(+)WIN55,212-2 augments interferon-β expression via peroxisome proliferator-activated receptor-α.
2012 - Study ~ Update on the role of cannabinoid receptors after ischemic stroke.
2012 - Study ~ Palmitoylethanolamide exerts neuroprotective effects in mixed neuroglial cultures and organotypic hippocampal slices via peroxisome proliferator-activated receptor-α.
2012 - Study ~ Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a ` murine model of acute lung injury: Role for the adenosine A(2A) receptor.
2012 - Study ~ Endocannabinoids limit excessive mast cell maturation and activation in human skin.
2012 - Study ~ The endocannabinoid system: a revolving plate in neuro-immune interaction in health and disease.
2012 - Study ~ Cannabinoid signalling regulates inflammation and energy balance: The importance of the brain-gut axis.
2012 - Study ~ The Role of Cannabinoids In Inflammatory Modulation of Allergic Respiratory Disorders, Inflammatory Pain and Ischemic Stroke.
2012 - Study ~ WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway.
2012 - Study ~ Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?
2012 - Study ~ Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors.
2012 - Study ~ Effects of palmitoylethanolamide on intestinal injury and inflammation caused by ischemia-reperfusion in mice.
2012 - Study ~ Differential migratory properties of monocytes isolated from human subjects naïve and non-naïve to Cannabis.
2012 - Study ~ Cannabinoid receptor-2-selective agonists improve recovery in experimental autoimmune encephalomyelitis.
2012 - Study ~ Anti-Inflammatory Effect of the Endocannabinoid Anandamide in Experimental Periodontitis and Stress in the Rat.
2012 - Study ~ Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions.
2012 - Study ~ Palmitoylethanolamide is a new possible pharmacological treatment for the inflammation associated with trauma.
2012 - Study ~ Endocannabinoids alleviate proinflammatory conditions by modulating innate immune response in muller glia during inflammation.
2012 - Study ~ Cannabinoids inhibit peptidoglycan-induced phosphorylation of NF-κB and cell growth in U87MG human malignant glioma cells.
2012 - Study ~ Differential Modulation by Delta(9)-Tetrahydrocannabinol (∆ (9)-THC) of CD40 Ligand (CD40L) Expression in Activated Mouse Splenic CD4(+) T cells.
2012 - Study ~ Cannabidiol treatment ameliorates ischemia/reperfusion renal injury in rats
2012 - Study ~ A cannabinoid type 2 receptor agonist attenuates blood-brain barrier damage and
neurodegeneration in a murine model of traumatic brain injury.
2012 - Study ~ Activation of Cannabinoid Receptor 2 reduces inflammation in acute experimental
pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms.
2012 - Study ~ N-acyl amines of docosahexaenoic acid and other n-3 polyunsatured fatty acids – From fishy endocannabinoids to potential leads
2012 - Study ~ N-arachidonoyl glycine induces macrophage apoptosis via GPR18
2012 - Study ~ Anti-Inflammatory Effect of the Endocannabinoid Anandamide in Experimental Periodontitis and Stress in the Rat
2012 - Study ~ Palmitoylethanolamide is a new possible pharmacological treatment for the inflammation associated with trauma .
2012 - Study ~ CD200-CD200R1 interaction contributes to neuroprotective effects of anandamide on experimentally induced inflammation
2012 - Study ~ Update on the endocannabinoid-mediated regulation of gelatinase release in arterial wall physiology and atherosclerotic pathophysiology.
2012 - Study ~ Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice.
2012 - Study ~ Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis
2012 - Study ~ Electroacupuncture reduces the expression of proinflammatory cytokines in inflamed skin tissues through activation of cannabinoid CB2 receptors.
2011 - Study ~ Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study.
2011 - Study ~ Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement.
2011 - Study ~ Evaluation of the Cyclooxygenase Inhibiting Effects of Six Major Cannabinoids Isolated from Cannabis sativa.
2011 - Study ~ Gut feelings about the endocannabinoid system.
2011 - Study ~ Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis.
2011 - Study ~ Local activation of cannabinoid CB1 receptors in the urinary bladder reduces the inflammation-induced sensitization of bladder afferents.
2011 - Study ~ Cannabinoid CB2 Receptors Contribute to Upregulation of β-endorphin in Inflamed Skin Tissues by Electroacupuncture.
2011 - Study ~ The Antinociceptive Effects of JWH-015 in Chronic Inflammatory Pain Are Produced by Nitric Oxide-cGMP-PKG-KATP Pathway Activation Mediated by Opioids.
2011 - Study ~ Cannabinoids and Innate Immunity: Taking a Toll on Neuroinflammation.
2011 - Study ~ Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation.
2011 - Study ~ Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress.
2011 - Study ~ GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils.
2011 - Study ~ Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation.
2011 - Study ~ Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ(9) -tetrahydrocannabinol in BV-2 microglial cells.
2011 - Study ~ Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death.
2011 - Study ~ Deletion of cannabinoid receptors 1 and 2 exacerbates APC function to increase inflammation and cellular immunity during influenza infection.
2011 - Study ~ A synthetic cannabinoid, CP55940, inhibits lipopolysaccharide-induced cytokine mRNA expression in a cannabinoid receptor-independent mechanism in rat cerebellar granule cells.
2011 - Study ~ Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes.
2011 - Study ~ Allergen Challenge Increases Anandamide in Bronchoalveolar Fluid of Patients With Allergic Asthma.
2011 - News ~ New metabolic pathway for controlling brain inflammation.2010 - Study ~ Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression.
2010 - Study ~ Cannabinoids and Viral Infections.
2010 - Study ~ US Patent Application 20100222437 - COMPOSITION CONTAINING NON-PSYCHOTROPIC CANNABINOIDS FOR THE TREATMENT OF INFLAMMATORY DISEASES.
2010 - Study ~ The endocannabinoid system as a target for the treatment of neurodegenerative disease.
2010 - Study ~ The effects of Delta-tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis.
2010 - Study ~ Regulatory Role of Cannabinoid Receptor 1 in Stress-Induced Excitotoxicity and Neuroinflammation.
2010- Study ~ Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion.
2010 - Study ~ WIN55212-2 ameliorates atherosclerosis associated with suppression of pro-inflammatory responses in ApoE-knockout mice.
2010 - Study ~ Beneficial effects of cannabinoids (CB) in a murine model of allergen-induced airway inflammation: Role of CB(1)/CB(2) receptors.
2010 - Study ~ Levels of endocannabinoids and palmitoylethanolamide and their pharmacological manipulation in chronic granulomatous inflammation in rats.
2010 - News ~ Hemp Oil Benefits for Skin.
2009 - Study - Cannabinoids, endocannabinoids, and related analogs in inflammation.
2009 - Study - Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats.
2009 - Study ~ Emerging Role of the CB2 Cannabinoid Receptor in Immune Regulation and Therapeutic Prospects.
2009 - Study ~ Cannabinoid CB2 Receptor Potentiates Obesity-Associated Inflammation, Insulin Resistance and Hepatic Steatosis.
2009 - Study ~ Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells.
2009 - Study ~ Ajulemic acid, a synthetic cannabinoid, increases formation of the endogenous proresolving and anti-inflammatory eicosanoid, lipoxin A4.
2009 - Study ~ Cannabinoids as Therapeutic Agents for Ablating Neuroinflammatory Disease.
2009 - Study ~ Cannabidiol Attenuates Cisplatin-Induced Nephrotoxicity by Decreasing Oxidative/Nitrosative Stress, Inflammation, and Cell Death.
2009 - Study ~ Cannabinoids as novel anti-inflammatory drugs.
2009 - Study ~ The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function.
2009 - Study ~ Endocannabinoid signalling as an anti-inflammatory therapeutic target in atherosclerosis: does it work?
2009 - Study ~ Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis.
2009 - News ~ How Hemp Seed Oil Can Help Your Arthritis.2008 - Study - Inflammation and aging: can endocannabinoids help?
2008 - Study - Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders.
2008 - Study ~ Anti-inflammatory cannabinoids in diet.
2008 - Study ~ Cannabinoid receptors in acute and chronic complications of atherosclerosis.
2008 - Study ~ Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats.
2008 - Study ~ Cannabinoid CB2 receptors in human brain inflammation.
2008- Study ~ Cannabinoid Modulation of Cutaneous A{delta} Nociceptors During Inflammation.
2008 - Study ~ Scientists are High on Idea that Cannabis Reduces Memory Impairment.
2008 - News - Marijuana reduces memory impairment.
2008 - News -  Why Cannabis Stems Inflammation.
2007 - Study ~ Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain
2007 - Study ~ Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis
2007 - Study ~ Cannabidiol in vivo blunts β-amyloid induced neuroinflammation by suppressing IL-1β and iNOS expression (Alzheimer's)
2007 - Study ~ Opposing control of cannabinoid receptor stimulation on amyloid-beta-induced reactive gliosis: in vitro and in vivo evidence.
2007 - Study ~ Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro
2007 - Study ~ Honokiol, a natural plant product, inhibits inflammatory signals and alleviates inflammatory arthritis.
2007 - Study ~ Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation
2007 - Study ~ The endocannabinoid system in targeting inflammatory neurodegenerative diseases
2007 - Study ~ Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain
2007 - Study ~ Cannabinoids and neuroprotection in motor-related disorders.
2007 - Study ~ A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain.
2007 - Interview ~ Endocannabinoids, cannabinoid receptors and inflammatory stress: an interview with Dr. Pál Pacher
2007 - News ~ Constituents Of Hashish And Marijuana May Help To Fight Inflammation And Allergies
2007 - News ~ Pot Chemical May Curb Inflammation
2007 - News ~ Endocannabinoids appear to play important role in regulating inflammation
2007 - News ~ Hippies vindicated: Human-produced cannabinoids have anti-inflammatory powers
2006 - Study ~ Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes2006 - Study ~ Involvement of the Cannabinoid CB2 Receptor and Its Endogenous Ligand 2- Arachidonoylglycerol in Oxazolone-Induced Contact Dermatitis in Mice
2006 - Study ~ The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells.
2006 - Study ~ Cannabinoid-Induced Immune Suppression and Modulation of Antigen-Presenting Cells
2006 - News ~ Anandamide, an endocannabinoid, protects neurons from inflammation after brain damage
2005 - Study ~ The cannabinoid receptor agonist WIN 55212-2 inhibits neurogenic inflammations in airway tissues.2005 - Study ~ Ajulemic acid (IP-751): Synthesis, proof of principle, toxicity studies, and clinical trials
2005 - Study ~ Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation
2005 - Study ~ Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson's disease.
2005 - Study ~ Endogenous cannabinoid receptor agonists inhibit neurogenic inflammations in guinea pig airways.
2004 - Study ~ New perspectives in the studies on endocannabinoid and cannabis: 2- arachidonoylglycerol as a possible novel mediator of inflammation
2004 - Study ~ Cannabinoids and neuroinflammation
2004 - Study ~ Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation.
2004 - Study ~ A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis.
2003 - Study ~ Inhibition of Inflammatory Hyperalgesia by Activation of Peripheral CB2 Cannabinoid Receptors
2003 - Study ~ Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model.
2002 - Study ~ Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat
2000 - Study ~ Endocannabinoids and fatty acid amides in cancer, inflammation and related disorders.
1999 - Study ~ 1′,1′-Dimethylheptyl-Δ-8-tetrahydrocannabinol-11-oic Acid: A Novel, Orally Effective Cannabinoid with Analgesic and Anti-inflammatory Properties.
1989 - Study ~ Antiinflammatory and antimicrobial compounds and compositions
United States Patent 4837228.
1988 - Study - Analgestic and anti-inflammatory activity of constittuents of cannabis sativa L.
1981 - Study ~ Biological activity of cannabichromene, its homologs and isomers.




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ANALGESIC AND ANTIINFLAMMATORY ACTIVITY OF CONSTITUENTS OF CANNABIS SATIVA L. (1988)
NFLAMMATION, Vol 12, No. 4, 1988 E.A. Formukong, A.T. Evans, and F.J. Evans
Department of Pharmacognosy, The School of Pharmacy University of London,
29-39 Brunswick Square London, WC11N 1AX, England 
Abstract---Two extracts of Cannabis sativa herb, one being cannabinoid--free (ethanol) and the other containing the cannabinoids (petroleum), were shown to inhibit PBQ- induced writhing in mouse when given orally and also to antagonize tetradecanoylphorbol acetate (TPA) -induced erythema of mouse skin when applied topically. With the exception of cannabinol (CBN) and delta-1-tetrahydrocannabinol (delta-1-THC), the cannabinoids and olivetol (their biosynthetic precursor) demonstrated activity in the PBQ test exhibiting their maximal effect at doses of about 100 mcg/kg. Delta-1-THC only became maximally effective in doses of 10 mg/kg.


This higher dose corresponded to that which induced catalepsy and is indicative of a central action. CBN produce a 40% inhibition of PBQ-induced writhing. Cannabidiol (CBD) was the most effective of the cannabinoids at doses of 100 mcg/kg. Doses of cannabinoids that were effective in the analgesic test orally were used topically to antagonize TPA-induced erythema of skin. The fact that delta-1-THC and CBN were the least effective in this test suggests a structural relationship between analgesic activity and antiinflammatory activity among the cannabinoids related to their peripheral actions and separate from the central effects of delta-1-THC.  
INTRODUCTION  
Various preparations of Cannabis sativa have been employed for their medicinal effects, including antipyretic, antirheumatic, antiallergic, and analgesic purposes. Extracts of Cannabis have been shown to possess analgesic activity, and delta-1-tetrahydrocannabinol (delta-1-THC), the psychoactive component of Cannabis has also been shown to possess this activity in various models. In addition, cannabinol (CBN) but not cannabidiol (CBD) was shown to exhibit analgesic activity in vivo.
It is possible that the antiinflammatory and antiasthmatic properties of this herb are mediated through effects on arachidonate metabolism. However, constituents of Cannabis are known to stimulate and inhibit prostaglandin (PG) release by influencing enzymes of this pathway.


A cannabinoid or an extract of Cannabis with little or no central effects could be of use therapeutically. In this paper, we have examined the antiinflammatory potential of two extracts of Cannabis, pure cannabinoids and olivetol (a cannabinoid biosynthetic precursor) in two models of inflammation, in an attempt to separate on a structural basis the peripheral from the central action of these phenolic drugs.  
MATERIALS AND METHODS  
The folowing were used: aspirin (Sigma Chemical Co., Poole, Dorset.), tripotassium citrate (analytical grade), all cannabinoids except CBG (Sigma), and CBG (Makor Chemicals, Jerusalem, Israel).
Preparation of Drugs: PBQ Test. Cannabinoids and cannabis extracts were suspended in a 1% ethanolic solution containing 2.5% w/v Tween. Aspirin was dissolved in a 40 mg/ml solution of tripotassium citrate.
Phenyl Benzoquinone Writhing (PBQ) and Preparation of PBQ Solution. A 0.04% solution of PBQ was prepared immediately before use by dissolving PBQ in warm ethanol and diluting with water at 40 degrees C bringing the ethanolic concentration to 5%. The bottle was stoppered, foil paper wrapped around it, and the solution maintained at 34 degrees C. Deterioration of the solution occurs if left exposed to light and air.
Administration of Drugs. Male CDI male (Charles River) weighing 18-20 g were starved overnight for the experiment. Animals were placed in a thermostatically controlled environment maintained at 34 degrees C. Mice were orally administered test drug 20 min before the intraperitoneal injection of PBQ (4 mg/kg). Five minutes after injection, a hand tally counter was used to record the number of stretching movements for each mouse in a 5-min period. Control animals were only administered the vehicle. Note less than five animals were used per dose.
Statistical Analysis. Results are expressed as mean percentage inhibition of control (+SEM) in the case of PBQ test. IC-50s were obtained from graphs relating probit percentage inhibition (ordinate) against log dose (abscissa). The IC-50 is that dose of drug which would inhibit PBQ-induced writhing by 50%.
Tetradecanoyl phorbol-acetate-induced (TPA) Erythema of Mouse Ear. In order to exclude the possibility of a central mechanism of action (see Discussion), compounds also were tested for their ability to inhibit TPA-induced erythema on mouse ears in 100% of the animals was chosen as the challenging dose for inhibition studies, measured 4 h after application.
Test drugs were dissolved in ethanol and 5 ul applied to the inner ear of the mouse 15 min before the application of 1 mcg TPA in 5 ul acetone. Only one dose of test dug was used for this experiment, 100 mcg/mcl ethanols, except trifluoperazine at 1 mg/5 ul. The other ear acted as a control.
The results were expressed as percentage inhibition, taken to mean the complete suppression of erythema in the test animals, as described in reference 19. 
RESULTS 
PBQ-Induced Writhing. CBD, CBG, olivetol, ethanolic extract, and petroleum spirit extract produced significant inhibition at doses up to 10 mg/kg (Figures 1-3). CBN was only marginally active.
Delta-1-THC was fully effective only at concentrations above 10 mg/kg Figure 2).
The ethanolic and petroleum extract, CBD, olivetol, CBG, and cannflavon were more potent than aspirin. The petroleum spirit extract was about four times more potent than the ethanolic extract, which was virtually equipotent with CBD. Cannflavon, isolated from the ethanolic extract was 14 times less potent than the ethanolic extract of the dried herb.
There was a decline in response following the administration of doses greater than 0.1 mg/kg of some substances. This is most evident in the bell shaped dose-response curve of the petroleum spirit extract. The activity of the ethanolic extract and CBD was also found to decrease slightly at higher dose levels.
TPA-Induced Erythema. In general, the ability of compounds to inhibit TPA-induced erythema correlated well with their potency in the PBQ-writhing test. Thus, CBN and delta-1-THC were the least active followed by CBG, CBD, and cannflavon. Again, the extracts were the most active (Table 3). Twenty-four hours after application, the ethanolic extract still produced 16% inhibition of TPA-induced erythema of the animals. All other substances were without activity after 24 h.
All substances were more active than trifluoperazine, 1 mg/5ul, a known phorbol ester antagonist both in vivo and in vitro (20).  
DISCUSSION
The PBQ-induced writhing response is believed to be produced by the liberation of endogenous substance(s), notably metabolites of the arachidonic cascade. However, the PBQ test is not specific for weak analgesics such as the nonsteroidal antiinflammatory drugs, as it also detects centrally active analgesics.
Therefore, in the elucidation of the action of the cannabinoids as inflammatory drugs, it was necessary to perform more than one test. In this case, peripheral rather than central action was confirmed in the mouse ear erythema assay.
TPA-induced erythema was inhibited by the extracts cannflavon, cannabinoids, and olivetol. The activity of TPA has been shown to be dependent upon PG release in mouse epidermis and mouse peritoneal macrophages possibly via the initial stimulation of protein kinase C (for a review see reference. It has also been shown that compounds that show moderate to very potent antiinflammatory potential in standard in vivo inflammation models will also inhibit TPA-induced edema of the mouse ear, and phorbol-ester-induced erythema.
It is possible that the cannabinoids and their extracts are inhibiting both PBQ-induced writhing and TPA-induced erythema by effects on arachidonate release and metabolism. Cannabinoids and olivetol have been shown to inhibit PG mobilization and synthesis.
The noncannabinoid constituents of Cannabis, for example, cannflavon, have been shown to be mainly cyclooxygenase inhibitors. Cannabinoids, however, stimulate and inhibit phospholipase A2 (PLA2) activity, as well as inducing an inhibition of cyclooxygenase and lipoxygenase. The activity of Cannabis herb or resin is complex, in that activities can be demonstrated on at least three major enzymes of the arachidonate cascade.
The mechanism by which delta-1-THC inhibits PBQ-induced writhing may differ from that of the other substances. At concentrations greater than 10 mg/kg, delta-1-THC may be inhibiting PBQ-induced writhing by acting on central rather than peripheral functions.
It is possible that prostaglandins modulate certain inhibitory pathways in the brain, bringing about an increase in the pain threshold. This dose of delta-1-THC is capable of bringing about the cataleptic effect , which is a standard test for central involvement. Central analgesics have higher efficacies than peripheral ones, and this may explain the effectiveness of delta-1-THC.
The central involvement of delta-1-THC is perhaps the primary reason why delta-1-THC was recognized as an analgesic before other cannabinoids.
Our results suggest that the response of the ethanolic extract cannot be solely due to cannflavon. Other structurally related phenolic substances, known to be present in this complex extract, may account for the higher activity seen either due to cumulative or synergistic effects upon cyclooxygenase.
The activity of the petroleum ether extract is likely to be largely due to the presence of CBD and CBN. GLC analysis of the extract has shown that this extract contained 14.13% CBD, 9.08% CBN, and 6.68% delta-1-THC. On the basis of our results, it is possible to separate the centrally active cannabinoid delta-1-THC from peripherally active compounds of the herbal extracts. An attempt has been made to differentiate them structurally .
It can be seen that the olivetolic nucleus together with a free C-5 hydroxyl group are structural requirements for peripheral effects, involving both cyclooxygenase and lipoxygenase inhibition.
Substances possessing this structure possess antiinflammatory and analgesic activities without central hallucinogenic effects. Delta-1-THC and CBN, which are cyclized derivatives exhibiting no C-5 hydroxyl moiety, have little if any peripheral action.
The traditional use of Cannabis as an analgesic, antiasthmatic, and antirheumatic drug is well established. Our results would suggest that cultivation of Cannabis plants rich in CBD and other phenolic substances would be useful not only as fiber-producing plants but also for medicinal purposes in the treatment of certain inflammatory disorders. ​