Neurobehavioral Disorders

Neuropharmacology. 2012 Oct;63(5):776-83. doi: 10.1016/j.neuropharm.2012.05.034. Epub 2012 May 30.

Cannabidiol administration after hypoxia-ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function.

Experimental Unit, Foundation for Biomedical Research, Madrid, Spain.
Cannabidiol (CBD) demonstrated short-term neuroprotective effects in the immature brain following hypoxia-ischemia (HI). We examined whether CBD neuroprotection is sustained over a prolonged period. Newborn Wistar rats underwent HI injury (10% oxygen for 120 min after left carotid artery electrocoagulation) and then received vehicle (HV, n = 22) or 1 mg/kg CBD (HC, n = 23). Sham animals were similarly treated (SV, n = 16 and SC, n = 16). The extent of brain damage was determined by magnetic resonance imaging, histological evaluation (neuropathological score, 0-5), magnetic resonance spectroscopy and Western blotting. Several neurobehavioral tests (RotaRod, cylinder rear test[CRT],and novel object recognition[NOR]) were carried out 30 days after HI (P37). CBD modulated brain excitotoxicity, oxidative stress and inflammation seven days after HI. We observed that HI led to long-lasting functional impairment, as observed in all neurobehavioral tests at P37, whereas the results of HC animals were similar to those of sham animals (all p < 0.05 vs. HV). CBD reduced brain infarct volume by 17% (p < 0.05) and lessened the extent of histological damage. No differences were observed between the SV and SC groups in any of the experiments. In conclusion, CBD administration after HI injury to newborn rats led to long-lasting neuroprotection, with the overall effect of promoting greater functional rather than histological recovery. These effects of CBD were not associated with any side effects. These results emphasize the interest in CBD as a neuroprotective agent for neonatal HI.
PMID: 22659086 [PubMed - indexed for MEDLINE]

Crit Rev Neurobiol. 2007;19(1):29-57.

Cerebellar-dependent learning as a neurobehavioral index of the cannabinoid system.

1Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA.

Delta-9-tetrahydrocannabinol (THC) is the primary psycho-active ingredient in Cannabis spp., the most widely used illicit drug in the United States. THC is an exogenous agonist of the central cannabinoid receptor (CB1), one of the most abundant G-coupled receptors in the mammalian brain. Although CB1 receptors are distributed throughout the brain, they are found at very high levels in the cerebellum. Despite the variety of disturbances associated with acute cannabis intoxication, including altered short-term memory, dissociation of thoughts, motor impairments, and paranoia, among others, a reliable index of cannabinoid system function has in large part eluded scientists. Thus, there is a demand in contemporary clinical neuroscience for methods sensitive to cannabinoid system function, not only for assessing how cannabis use influences human information processing, but also to assess the involvement of the endocannabinoid system (ECS) in clinical disease and evaluate the effects of CB1-based drug therapies. The purpose of the present article, therefore, is to address this current need by integrating two separate literatures. The first literature demonstrates that the ECS mediates synaptic plasticity, specifically, long-term depression (LTD) of parallel fibers at the parallel fiber-Purkinje junction in the cerebellar cortex. The second literature suggests that LTD at this junction is necessary for the acquisition of the primary dependent variable in delay eyeblink conditioning (EBC)--the exhibition of temporally measured conditioned responses. These two literatures are integrated by proposing an updated EBC circuit that incorporates the CB1 receptor and the endogenous cannabinoids. Finally, the implications of the model is discussed in consideration of recent evidence from CB1 knockout mice, human cannabis users, and schizophrenia patients, with the expectation that translational research on the cannabinoid system will be advanced.

PMID: 19166390 [PubMed - indexed for MEDLINE]

Tourette Syndrome

Neuropsychopharmacology. 2003 Feb;28(2):384-8.

Treatment of Tourette Syndrome with Δ9-Tetrahydrocannabinol (Δ 9-THC): No Influence on Neuropsychological Performance.

Müller-Vahl KR, Prevedel H, Theloe K, Kolbe H, Emrich HM, Schneider U.

Department of Clinical Psychiatry and Psychotherapy, Medical School Hannover, Hannover, Germany.

This email address is being protected from spambots. You need JavaScript enabled to view it.

Previous studies provide evidence that marijuana (Cannabis sativa) and Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient of marijuana, respectively, are effective in the treatment of tics and behavioral problems in Tourette syndrome (TS). It, therefore, has been speculated that the central cannabinoid receptor system might be involved in TS pathology. However, in healthy marijuana users there is an ongoing debate as to whether the use of cannabis causes acute and/or long-term cognitive deficits. In this randomized double-blind placebo-controlled study, we investigated the effect of a treatment with up to 10 mg Δ9-THC over a 6-week period on neuropsychological performance in 24 patients suffering from TS. During medication and immediately as well as 5-6 weeks after withdrawal of Δ9-THC treatment, no detrimental effect was seen on learning curve, interference, recall and recognition of word lists, immediate visual memory span, and divided attention. Measuring immediate verbal memory span, we even found a trend towards a significant improvement during and after treatment. Results from this study corroborate previous data suggesting that in patients suffering from TS, treatment with Δ9-THC causes neither acute nor long-term cognitive deficits. Larger and longer-duration controlled studies are recommended to provide more information on the adverse effect profile of THC in patients suffering from TS.

PMID: 12589392 [PubMed - indexed for MEDLINE]


Post Traumatic Stress Disorder (PTSD)

Neuropsychopharmacology. 2007 May;32(5):1032-41. Epub 2006 Oct 18.

Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task.

Varvel SA, Wise LE, Niyuhire F, Cravatt BF, Lichtman AH.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.

 Recent reports have demonstrated that disruption of CB(1) receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (-/-) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAH-compromised mice also exhibited a significant increase in acquisition rate. The CB(1) receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB(1) receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB(1) receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.

PMID: 17047668 [PubMed - indexed for MEDLINE]



Learn Mem. 2006 Jul-Aug;13(4):426-30.

Aversive Memory Reactivation Engages in the Amygdala Only Some Neurotransmitters Involved in Consolidation.

Bucherelli C, Baldi E, Mariottini C, Passani MB, Blandina P.

Dipartimento di Scienze Fisiologiche, Universitá di Firenze, 50134 Firenze, Italy.

Consolidation refers to item stabilization in long-term memory. Retrieval renders a consolidated memory sensitive, and a "reconsolidation" process has been hypothesized to keep the original memory persistent. Some authors could not detect this phenomenon. Here we show that retrieved contextual fear memory is vulnerable to amnesic treatments and that the amygdala is critically involved. Cholinergic and histaminergic systems seem to modulate only consolidation, whereas cannabinoids are involved in both consolidation and reactivation. The lability of retrieved memory affords opportunities to treat disorders such as phobias, post-traumatic stress, or chronic pain, and these results help searching for appropriate therapeutic targets.

PMID: 16882859 [PubMed - indexed for MEDLINE]



Chronic Pain or Pain Management

Mol Pain. 2009 Oct 8;5:59.

Dynamic Regulation of the Endocannabinoid System: Implications for Analgesia.

Sagar DR, Gaw AG, Okine BN, Woodhams SG, Wong A, Kendall DA, Chapman V.

School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK.

This email address is being protected from spambots. You need JavaScript enabled to view it.

The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthetic pathways for endocannabinoids are expressed by various cell types, multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid-based analgesics.

PMCID: PMC2770047, PMID: 19814807 [PubMed - in process]



Mol Pain. 2009 Mar 10;5:11.

Gz Mediates the Long-Lasting Desensitization of Brain CB1 Receptors and is Essential for Cross-Tolerance with Morphine.

Garzón J, de la Torre-Madrid E, Rodríguez-Muñoz M, Vicente-Sánchez A, Sánchez-Blázquez P.

Instituto Cajal, CSIC, Madrid, Spain.

This email address is being protected from spambots. You need JavaScript enabled to view it.

BACKGROUND: Although the systemic administration of cannabinoids produces antinociception, their chronic use leads to analgesic tolerance as well as cross-tolerance to morphine. These effects are mediated by cannabinoids binding to peripheral, spinal and supraspinal CB1 and CB2 receptors, making it difficult to determine the relevance of each receptor type to these phenomena. However, in the brain, the CB1 receptors (CB1Rs) are expressed at high levels in neurons, whereas the expression of CB2Rs is marginal. Thus, CB1Rs mediate the effects of smoked cannabis and are also implicated in emotional behaviors. We have analyzed the production of supraspinal analgesia and the development of tolerance at CB1Rs by the direct injection of a series of cannabinoids into the brain. The influence of the activation of CB1Rs on supraspinal analgesia evoked by morphine was also evaluated.

RESULTS: Intracerebroventricular (icv) administration of cannabinoid receptor agonists, WIN55,212-2, ACEA or methanandamide, generated a dose-dependent analgesia. Notably, a single administration of these compounds brought about profound analgesic tolerance that lasted for more than 14 days. This decrease in the effect of cannabinoid receptor agonists was not mediated by depletion of CB1Rs or the loss of regulated G proteins, but, nevertheless, it was accompanied by reduced morphine analgesia. On the other hand, acute morphine administration produced tolerance that lasted only 3 days and did not affect the CB1R. We found that both neural mu-opioid receptors (MORs) and CB1Rs interact with the HINT1-RGSZ module, thereby regulating pertussis toxin-insensitive Gz proteins. In mice with reduced levels of these Gz proteins, the CB1R agonists produced no such desensitization or morphine cross-tolerance. On the other hand, experimental enhancement of Gz signaling enabled an acute icv administration of morphine to produce a long-lasting tolerance at MORs that persisted for more than 2 weeks, and it also impaired the analgesic effects of cannabinoids.

CONCLUSION: In the brain, cannabinoids can produce analgesic tolerance that is not associated with the loss of surface CB1Rs or their uncoupling from regulated transduction. Neural specific Gz proteins are essential mediators of the analgesic effects of supraspinal CB1R agonists and morphine. These Gz proteins are also responsible for the long-term analgesic tolerance produced by single doses of these agonists, as well as for the cross-tolerance between CB1Rs and MORs.

PMCID: PMC2657119, PMID: 19284549 [PubMed - indexed for MEDLINE]



Neuropsychiatr Dis Treat. 2008 Oct;4(5):847-53.

Cannabinoids in the Management of Spasticity Associated with Multiple Sclerosis.

Malfitano AM, Proto MC, Bifulco M.

Dipartimento di Scienze, Farmaceutiche, Università degli Studi di Salerno.

The endocannabinoid system and cannabinoid-based treatments have been involved in a wide number of diseases. In particular, several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis (MS). In this study we highlight the main findings reported in literature about the relevance of cannabinoid drugs in the management and treatment of MS. An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of MS, including spasticity and pain. In this report we focus on the effects of cannabinoids in the relief of spasticity describing the main findings in vivo, in the mouse experimental allergic encephalomyelitis model of MS. We report on the current treatments used to control MS symptoms and the most recent clinical studies based on cannabinoid treatments, although long-term studies are required to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

PMID: PMC2626929, PMID: 19183777 [PubMed - in process]



Multiple Sclerosis

Trends Pharmacol Sci. 2009 Aug;30(8):411-20. Epub 2009 Jul 14.

The Endocannabinoid System of the Skin in Health and Disease: Novel Perspectives and Therapeutic Opportunities.

Bíró T, Tóth BI, Haskó G, Paus R, Pacher P.

Department of Physiology, University of Debrecen, Research Center for Molecular Medicine, Debrecen 4032, Hungary.

This email address is being protected from spambots. You need JavaScript enabled to view it.

The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their G-protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease. Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes (e.g. proliferation, growth, differentiation, apoptosis and cytokine, mediator or hormone production of various cell types of the skin and appendages, such as the hair follicle and sebaceous gland). It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).

PMID: PMC2757311, PMID: 19608284 [PubMed - indexed for MEDLINE]



Neuropsychiatr Dis Treat. 2008 Oct;4(5):847-53.

Cannabinoids in the Management of Spasticity Associated with Multiple Sclerosis.

Malfitano AM, Proto MC, Bifulco M.

Dipartimento di Scienze, Farmaceutiche, Università degli Studi di Salerno.

The endocannabinoid system and cannabinoid-based treatments have been involved in a wide number of diseases. In particular, several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis (MS). In this study we highlight the main findings reported in literature about the relevance of cannabinoid drugs in the management and treatment of MS. An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of MS, including spasticity and pain. In this report we focus on the effects of cannabinoids in the relief of spasticity describing the main findings in vivo, in the mouse experimental allergic encephalomyelitis model of MS. We report on the current treatments used to control MS symptoms and the most recent clinical studies based on cannabinoid treatments, although long-term studies are required to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

PMID: PMC2626929, PMID: 19183777 [PubMed - in process]



Endocr Metab Immune Disord Drug Targets. 2008 Sep;8(3):159-72.

Cannabinoids as Therapeutic Agents for Ablating Neuroinflammatory Disease.

Cabral GA, Griffin-Thomas L.

Department of Microbiology and Immunology, Virginia Commonwealth University, School of Medicine, 1101 E. Marshall Street, Richmond, Virginia 23298-0678 USA.

This email address is being protected from spambots. You need JavaScript enabled to view it.

Cannabinoids have been reported to alter the activities of immune cells in vitro and in vivo. These compounds may serve as ideal agents for adjunct treatment of pathological processes that have a neuroinflammatory component. As highly lipophilic molecules, they readily access the brain. Furthermore, they have relatively low toxicity and can be engineered to selectively target cannabinoid receptors. To date, two cannabinoid receptors have been identified, characterized and designated CB(1) and CB(2). CB(1) appears to be constitutively expressed within the CNS while CB(2) apparently is induced during inflammation. The inducible nature of expression of CB(2) extends to microglia, the resident macrophages of the brain that play a critical role during early stages of inflammation in that compartment. Thus, the cannabinoid-cannabinoid receptor system may prove therapeutically manageable in ablating neuropathogenic disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, HIV encephalitis, closed head injury, and granulomatous amebic encephalitis.

PMID: PMC2750822, PMID: 18782012 [PubMed - indexed for MEDLINE]




Methicillin-Resistant Staphylococcus Aureus (MRSA)

J Nat Prod. 2008 Aug;71(8):1427-30. Epub 2008 Aug 6.

Antibacterial Cannabinoids from Cannabis Sativa: a structure-activity study.

Appendino G, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM.

Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, 28100 Novara, Italy.

This email address is being protected from spambots. You need JavaScript enabled to view it.

Marijuana (Cannabis sativa) has long been known to contain antibacterial cannabinoids, whose potential to address antibiotic resistance has not yet been investigated. All five major cannabinoids (cannabidiol (1b), cannabichromene (2), cannabigerol (3b), Delta (9)-tetrahydrocannabinol (4b), and cannabinol (5)) showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance. Activity was remarkably tolerant to the nature of the prenyl moiety, to its relative position compared to the n-pentyl moiety (abnormal cannabinoids), and to carboxylation of the resorcinyl moiety (pre-cannabinoids). Conversely, methylation and acetylation of the phenolic hydroxyls, esterification of the carboxylic group of pre-cannabinoids, and introduction of a second prenyl moiety were all detrimental for antibacterial activity. Taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.

PMID: 18681481 [PubMed - indexed for MEDLINE]




J Leukoc Biol. 2008 Mar;83(3):785-96. Epub 2007 Dec 11.

Targeted Deletion of Cannabinoid Receptors CB1 and CB2 Produced Enhanced Inflammatory Responses to Influenza A/PR/8/34 in the Absence and Presence of Δ9-Tetrahydrocannabinol.

Buchweitz JP, Karmaus PW, Williams KJ, Harkema JR, Kaminski NE.

Department of Pharmacology and Toxicology, and Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.

We have previously reported that Δ9-tetrahydrocannabinol (Δ9-THC)-treated mice challenged with influenza virus A/PR/8/34 (PR8) developed increased viral hemagglutinin 1 (H1) mRNA levels and decreased monocyte and lymphocyte recruitment to the pulmonary airways when compared with mice challenged with PR8 alone. The objective of the present study was to examine the role of cannabinoid (CB(1)/CB(2)) receptors in mediating the effects of Δ9-THC on immune and epithelial cell responses to PR8. In the current study, Δ9-THC-treated CB(1)/CB(2) receptor null (CB(1)-/-/CB(2)-/-) and wild-type mice infected with PR8 had marked increases in viral H1 mRNA when compared with CB(1)-/-/CB(2)-/- and wild-type mice challenged with PR8 alone. However, the magnitude of the H1 mRNA levels was greatly reduced in CB(1)-/-/CB(2)-/- mice as compared with wild-type mice. In addition, Δ9-THC-treated CB(1)-/-/CB(2)-/- mice infected with PR8 had increased CD4+ T cells and IFN-gamma in bronchoalveolar lavage fluid with greater pulmonary inflammation when compared with Delta(9)-THC-treated wild-type mice infected with PR8. Δ9-THC treatment of CB(1)-/-/CB(2)-/- mice in the presence or absence of PR8 challenge also developed greater amounts of mucous cell metaplasia in the affected bronchiolar epithelium. Collectively, the immune and airway epithelial cell responses to PR8 challenge in Δ9-THC-treated CB(1)-/-/CB(2)-/- and wild-type mice indicated the involvement of CB(1)/CB(2) receptor-dependent and -independent mechanisms.

PMCID: 18073275 [PubMed - indexed for MEDLINE]



J Pharmacol Exp Ther. 2007 Nov;323(2):675-83. Epub 2007 Aug 28.

Modulation of Airway Responses to Influenza A/PR/8/34 by Δ9-Tetrahydrocannabinol in C57BL/6 Mice

Buchweitz JP, Karmaus PW, Harkema JR, Williams KJ, Kaminski NE.

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824-1317, USA.

Δ9-tetrahydrocannabinol (Δ9-THC) has been widely established as a modulator of host immune responses. Accordingly, the objective of the present study was to examine the effects of Δ9-THC on the immune response within the lungs and associated changes in the morphology of the bronchiolar epithelium after one challenge with a nonlethal dose of the influenza virus A/PR/8 (PR8). C57BL/6 mice were treated by oral gavage with Δ9-THC and/or vehicle (corn oil) for 5 consecutive days. On day 3, mice were instilled intranasally with 50 plaque-forming units of PR8 and/or vehicle (saline) 4 h before Δ9-THC exposure. Mice were subsequently killed 7 and 10 days postinfection (dpi). Viral hemagglutinin 1 (H1) mRNA levels in the lungs were increased in a dose-dependent manner with Δ9-THC treatment. Enumeration of inflammatory cell types in bronchoalveolar lavage fluid showed an attenuation of macrophages and CD4(+) and CD8(+) T cells in Δ9-THC-treated mice compared with controls. Likewise, the magnitude of inflammation and virus-induced mucous cell metaplasia, as assessed by histopathology, was reduced in Δ9-THC-treated mice by 10 dpi. Collectively, these results suggest that Δ9-THC treatment increased viral load, as assessed by H1 mRNA levels, through a decrease in recruitment of macrophages and lymphocytes, particularly CD4(+) and CD8(+) T cells, to the lung.

PMCID: 17726158 [PubMed - indexed for MEDLINE]




High Blood Pressure

Br J Pharmacol. 2009 Jan;156(1):94-104.

Acute Hypertension Reveals Depressor and Vasodilator Effects of Cannabinoids in Conscious Rats.

Ho WS, Gardiner SM.

School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.

This email address is being protected from spambots. You need JavaScript enabled to view it.

BACKGROUND AND PURPOSE: The cardiovascular effects of cannabinoids can be influenced by anesthesia and can differ in chronic hypertension, but the extent to which they are influenced by acute hypertension in conscious animals has not been determined.

EXPERIMENTAL APPROACH: We examined cardiovascular responses to intravenous administration of anandamide and the synthetic cannabinoid, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzox azin-6-yl]-1-naphthalenylmethanone (WIN55212-2), in conscious male Wistar rats made acutely hypertensive by infusion of angiotensin II (AII) and arginine vasopressin (AVP). Rats were chronically instrumented for measurement of arterial blood pressure and vascular conductances in the renal, mesenteric and hindquarters beds.

KEY RESULTS: Anandamide dose-dependently decreased the mean arterial blood pressure of rats made hypertensive by AII-AVP infusion, but not normotensive rats. Interestingly, acute hypertension also revealed a hypotensive response to WIN55212-2, which caused hypertension in normotensive animals. The enhanced depressor effects of the cannabinoids in acute hypertension were associated with increased vasodilatation in hindquarters, renal and mesenteric vascular beds. Treatment with URB597, which inhibits anandamide degradation by fatty acid amide hydrolase, potentiated the depressor and mesenteric vasodilator responses to anandamide. Furthermore, haemodynamic responses to WIN55212-2, but not to anandamide, were attenuated by the CB(1) receptor antagonist, AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide].

CONCLUSIONS AND IMPLICATIONS: These results broadly support the literature showing that the cardiovascular effects of cannabinoids can be exaggerated in hypertension, but highlight the involvement of non-CB(1) receptor-mediated mechanisms in the actions of anandamide.

PMCID: PMC2697765, PMID: 19133994 [PubMed - indexed for MEDLINE]



World J Gastroenterol. 2008 Oct 28;14(40):6109-14.

Role of Cannabinoids in Chronic Liver Diseases.

Parfieniuk A, Flisiak R.

Cannabinoids are a group of compounds acting primarily via CB1 and CB2 receptors. The expression of cannabinoid receptors in normal liver is low or absent. However, many reports have proven up-regulation of the expression of CB1 and CB2 receptors in hepatic myofibroblasts and vascular endothelial cells, as well as increased concentration of endocannabinoids in liver in the course of chronic progressive liver diseases. It has been shown that CB1 receptor signaling exerts profibrogenic and proinflammatory effects in liver tissue, primarily due to the stimulation of hepatic stellate cells, whereas the activation of CB2 receptors inhibits or even reverses liver fibrogenesis. Similarly, CB1 receptor stimulation contributes to progression of liver steatosis. In end-stage liver disease, the endocannabinoid system has been shown to contribute to hepatic encephalopathy and vascular effects, such as portal hypertension, splanchnic vasodilatation, relative peripheral hypotension and probably cirrhotic cardiomyopathy. So far, available evidence is based on cellular cultures or animal models. Clinical data on the effects of cannabinoids in chronic liver diseases are limited. However, recent studies have shown the contribution of cannabis smoking to the progression of liver fibrosis and steatosis. Moreover, controlling CB1 or CB2 signaling appears to be an attractive target in managing liver diseases.

PMCID: PMC2761570, PMID: 18985799 [PubMed - indexed for MEDLINE]



Hypertension. 2008 Oct;52(4):601-7. Epub 2008 Sep 8.

Modulation of the Endocannabinoid System in Cardiovascular Disease: Therapeutic Potential and Limitations.

Pacher P, Mukhopadhyay P, Mohanraj R, Godlewski G, Bátkai S, Kunos G.

Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9413, USA.

This email address is being protected from spambots. You need JavaScript enabled to view it.

PMCID: PMC2568884, PMID: 18779440 [PubMed - indexed for MEDLINE]




Prog Retin Eye Res. 2008 Sep;27(5):501-26. Epub 2008 Aug 3.

Endocannabinoids in the Retina: From Marijuana to Neuroprotection.

Yazulla S.

Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY 11794-5230, United States. stephen.

This email address is being protected from spambots. You need JavaScript enabled to view it.

The active component of the marijuana plant Cannabis sativa, Δ9-tetrahydrocannabinol (THC), produces numerous beneficial effects, including analgesia, appetite stimulation and nausea reduction, in addition to its psychotropic effects. THC mimics the action of endogenous fatty acid derivatives, referred to as endocannabinoids. The effects of THC and the endocannabinoids are mediated largely by metabotropic receptors that are distributed throughout the nervous and peripheral organ systems. There is great interest in endocannabinoids for their role in neuroplasticity as well as for therapeutic use in numerous conditions, including pain, stroke, cancer, obesity, osteoporosis, fertility, neurodegenerative diseases, multiple sclerosis, glaucoma and inflammatory diseases, among others. However, there has been relatively far less research on this topic in the eye and retina compared with the brain and other organ systems. The purpose of this review is to introduce the "cannabinergic" field to the retinal community. All of the fundamental works on cannabinoids have been performed in non-retinal preparations, necessitating extensive dependence on this literature for background. Happily, the retinal cannabinoid system has much in common with other regions of the central nervous system. For example, there is general agreement that cannabinoids suppress dopamine release and presynaptically reduce transmitter release from cones and bipolar cells. How these effects relate to light and dark adaptations, receptive field formation, temporal properties of ganglion cells or visual perception are unknown. The presence of multiple endocannabinoids, degradative enzymes with their bioactive metabolites, and receptors provides a broad spectrum of opportunities for basic research and to identify targets for therapeutic application to retinal diseases.

PMCID: PMC2584875, PMID: 18725316 [PubMed - indexed for MEDLINE]



Pharmacol Rev. 2006 Sep;58(3):389-462.

The Endocannabinoid System as an Emerging Target of Pharmacotherapy.

Pacher P, Bátkai S, Kunos G.

Laboratory of Physiological Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Room 2S-24, Bethesda, MD 20892-9413, USA.

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB(1) receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB(1) receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB(2) receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients' need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

PMCID: PMC2241751, PMID: 16968947 [PubMed - indexed for MEDLINE]



Br J Ophthalmol. 2004 May;88(5):708-13.

Cannabinoids and Glaucoma.

Tomida I, Pertwee RG, Azuara-Blanco A.

Department of Ophthalmology, Aberdeen Royal Infirmary, University of Aberdeen, UK.

Glaucoma is one of the leading causes of blindness in the world. In spite of the diverse therapeutic possibilities, new and better treatments for glaucoma are highly desirable. Cannabinoids effectively lower the intraocular pressure (IOP) and have neuroprotective actions. Thus, they could potentially be useful in the treatment of glaucoma. The purpose of this article is to provide the reader with an overview of the latest achievements in research into the potential use of cannabinoids for glaucoma.

PMCID: PMC1772142, PMID: 15090428 [PubMed - indexed for MEDLINE]




Gastro Intestinal Reflux Disease (GERD)

J Neurosci. 2009 Feb 4;29(5):1554-64.

CB1 receptors mediate the analgesic effects of cannabinoids on colorectal distension-induced visceral pain in rodents.

Brusberg M, Arvidsson S, Kang D, Larsson H, Lindström E, Martinez V.

Biosciences, AstraZeneca R&D Mölndal, Mölndal SE-431 83, Sweden.

Activation of cannabinoid receptors (CB(1), CB(2) and GPR(55)) produces analgesic effects in several experimental pain models, including visceral pain arising from the gastrointestinal tract. We assessed the role of CB(1), CB(2), and GPR(55) receptors and the endogenous cannabinoid system on basal pain responses and acute mechanical hyperalgesia during colorectal distension (CRD) in rodents. The effects of cannabinoid receptor agonists and antagonists on pain-related responses to CRD were assessed in rats and in wild-type and CB(1) receptor knock-out mice. The dual CB(1/2) agonist, WIN55,212-2, and the peripherally acting CB(1)-selective agonist, SAB-378, inhibited pain-related responses to repetitive noxious CRD (80 mmHg) in a dose-related manner in rats. The analgesic effects of WIN55,212-2 and SAB-378 were blocked by the selective CB(1) antagonist SR141716, but were not affected by the selective CB(2) antagonist SR144528. SR141716, per se, increased the responses to repetitive noxious CRD, indicative of hyperalgesia, and induced pain-related responses during non-noxious CRD (20 mmHg), indicative of allodynia. The cannabinoid receptor agonists anandamide, virodhamine and O-1602 had no effect. At analgesic doses, WIN55,212-2 did not affect colonic compliance. In accordance to the rat data, WIN55,212-2 produced analgesia, whereas SR141716 induced hyperalgesia, during noxious CRD (55 mmHg) in wild-type but not in CB(1)-knock-out mice. These data indicate that peripheral CB(1) receptors mediate the analgesic effects of cannabinoids on visceral pain from the gastrointestinal tract. The allodynic and hyperalgesic responses induced by SR141716 suggest the existence of an endogenous cannabinoid tone and the activation of CB(1) receptors during noxious CRD.

PMID: 19193902 [PubMed - indexed for MEDLINE]



Mayo Clin Proc. 2009;84(1):76-8.

Cannabinoid Hyperemesis Relieved by Compulsive Bathing.

Chang YH, Windish DM.

Yale Internal Medicine Primary Care Office, 64 Robbins Street, Waterbury, CT 06708, USA.

This email address is being protected from spambots. You need JavaScript enabled to view it.

Cannabinoid hyperemesis is a clinical syndrome characterized by repeated vomiting and associated learned compulsive hot water bathing behavior due to long-term marijuana use. Research has identified type 1 cannabinoid receptors in the intestinal nerve plexus that have an inhibitory effect on gastrointestinal motility. This inhibitory effect may lead to hyperemesis in marijuana users. The thermoregulatory role of endocannabinoids may be responsible for the patient's need to take hot showers. We report 2 cases of cannabinoid hyperemesis that demonstrate this unusual adverse effect of marijuana use.

PMCID: PMC2664574, PMID: 19121257 [PubMed - indexed for MEDLINE]



Br J Pharmacol. 2008 Nov;155(5):681-9. Epub 2008 Jul 14.

Inhibitory Effect of Salvinorin A, from Salvia Divinorum, on Ileitis-Induced Hypermotility: Cross-Talk Between Kappa-Opioid and Cannabinoid CB(1) Receptors.

Capasso R, Borrelli F, Cascio MG, Aviello G, Huben K, Zjawiony JK, Marini P, Romano B, Di Marzo V, Capasso F, Izzo AA.

Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.

This email address is being protected from spambots. You need JavaScript enabled to view it.

BACKGROUND AND PURPOSE: Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of kappa-opioid receptors (KORs). However, this compound may have target(s) other than the KORs in the inflamed gut. Because intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, in the present study we investigated the possible involvement of the endogenous cannabinoid system in salvinorin A-induced delay in motility in the inflamed gut.

EXPERIMENTAL APPROACH: Motility in vivo was measured by evaluating the distribution of a fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; direct or indirect activity at cannabinoid receptors was evaluated by means of binding, enzymic and cellular uptake assays.

KEY RESULTS: Salvinorin A as well as the KOR agonist U-50488 reduced motility in croton oil treated mice. The inhibitory effect of both salvinorin A and U-50488 was counteracted by the KOR antagonist nor-binaltorphimine and by the cannabinoid CB(1) receptor antagonist rimonabant. Rimonabant, however, did not counteract the inhibitory effect of salvinorin A on motility in control mice. Binding experiments showed very weak affinity of salvinorin A for cannabinoid CB(1) and CB(2) and no inhibitory effect on 2-arachidonoylglycerol and anandamide hydrolysis and cellular uptake.

CONCLUSIONS AND IMPLICATIONS: The inhibitory effect of salvinorin A on motility reveals a functional interaction between cannabinoid CB(1) receptors and KORs in the inflamed--but not in the normal--gut in vivo.

PMCID: PMC2584932, PMID: 18622408 [PubMed - indexed for MEDLINE]