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The Science of Marijuana
Each title links to the scientific abstract of each of theses studies.
Cannabinoids in medicine: A review of their therapeutic potential

Ben Amar M.

Substance Abuse Program, Faculties of Continuing Education and Graduate Studies, University of Montreal, C.P. 6128, succursale Centre-ville, Montreal, Que. H3C 3J7, Canada.

In order to assess the current knowledge on the therapeutic potential of cannabinoids, a meta-analysis was performed through Medline and PubMed up to July 1, 2005. The key words used were cannabis, marijuana, marihuana, hashish, hashich, haschich, cannabinoids, tetrahydrocannabinol, THC, dronabinol, nabilone, levonantradol, randomised, randomized, double-blind, simple blind, placebo-controlled, and human. The research also included the reports and reviews published in English, French and Spanish. For the final selection, only properly controlled clinical trials were retained, thus open-label studies were excluded. Seventy-two controlled studies evaluating the therapeutic effects of cannabinoids were identified. For each clinical trial, the country where the project was held, the number of patients assessed, the type of study and comparisons done, the products and the dosages used, their efficacy and their adverse effects are described. Cannabinoids present an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer and AIDS), analgesics, and in the treatment of multiple sclerosis, spinal cord injuries, Tourette's syndrome, epilepsy and glaucoma.

Journal of Ethnobotanicals, March 2006



Cannabis and Tobacco Smoke are Not Equally Carcinogenic

Robert Melamede

Harm Reduction Journal, 18 Oct., 2005

Tobacco has dramatic negative consequences for those who smoke it. In addition to its high addiction potential [1], tobacco is causally associated with over 400,000 deaths yearly in the United States, and has a significant negative effect on health in general [2]. More specifically, over 140,000 lung-related deaths in 2001 were attributed to tobacco smoke [3]. Comparable consequences would naturally be expected from cannabis smoking since the burning of plant material in the form of cigarettes generates a large variety of compounds that possess numerous biological activities [4].

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Pharmacokinetics and Pharmacodynamics of Cannabinoids

Franjo Grotenhermen

Nova-Institut, Hurth, Germany

Δ9-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms.
Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15 to 30 minutes, and taper off within 2 to 3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30 to 90 minutes, reach their maximum after 2 to 3 hours and last for about 4 to 12 hours, depending on dose and specific effect.
At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.

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Cannabinoids in anaesthesia and pain therapy

Azad S.C., Rammes G.

Department of Anaesthesiology, Pain Management Unit, Klinikum Grosshadern, Ludwig-Maximilians-Universitat Munchen, Munich, Germany Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany Clinical Neuropharmacology Group, Max-Planck-Institut fur Psychiatrie, Munich, Germany.

Cannabinoids have been known for their analgesic, anxiolytic, antiemetic and antispastic properties for many centuries. Since an endogenous cannabinoid system has been identified in the past two decades, cannabinoids have also become the focus of interest in western medicine. This review summarizes preclinical and clinical studies on the role of the endocannabinoid system and exogenous cannabinoids in anaesthesia and pain management.
RECENT FINDINGS: It has recently been shown that the endocannabinoid system is involved in the effects of the widely used anaesthetic drug propofol. In terms of nociception, preclinical data suggest that the endocannabinoid system plays an important role in the control of synaptic transmission and synaptic plasticity in pain pathways. In patients, the treatment of acute pain often requires relatively high doses of cannabinoids, which are associated with considerable side-effects such as dizziness and sedation. In contrast, preclinical and clinical data suggest that lower doses of cannabinoids may be effective for the treatment of allodynia and hyperalgesia in neuropathic pain. In multiple sclerosis, cannabinoids have been shown to have beneficial effects on spasticity, pain, tremor and bladder dysfunction.
SUMMARY: In general, the results of the very few well-conducted clinical trials often diverge from the highly interesting and promising findings of preclinical studies. Taken together, the most recent preclinical and clinical data suggest that cannabinoids should be applied as low-dose co-analgesics to inhibit neuroplasticity and central sensitization rather than as analgesics in acute pain.

Opinions in Anaesthesia, August 2005



Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404

La Rana G., Russo R., Campolongo P., Bortolato M., Mangieri R.A., Cuomo V., Iacono A., Mattace Raso G., Meli R., Piomelli D., Calignano A.

University of Naples - IT.

The endocannabinoid system may serve important functions in the central and peripheral regulation of pain. In the present study, we investigated the effects of the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide] on rodent models of acute and persistent nociception (intraplantar formalin injection in the mouse), neuropathic pain (sciatic nerve ligation in the rat) and inflammatory pain (complete Freund's adjuvant injection in the rat). In the formalin model, administration of AM404 (1-10 mg-kg(-1), intraperitoneal, i.p.) elicited dose-dependent antinociceptive effects, which were prevented by the CB1 cannabinoid receptor antagonist rimonabant (SR141716A; 1 mg-kg(-1), i.p.), but not by the CB2 antagonist SR144528 (1 mg-kg(-1), i.p.) or the vanilloid antagonist capsazepine (30 mg-kg(-1), i.p.). Comparable effects were observed with UCM707 [N-(3-furylmethyl)-eicosa-5,8,11,14-tetraenamide], another anandamide transport inhibitor. In both the chronic constriction injury (CCI) and complete Freund's adjuvant (CFA) model, daily treatment with AM404 (1-10 mg-kg(-1), subcutaneous, s.c.) for 14 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single administration of rimonabant (1 mg-kg(-1), i.p.) and was accompanied by decreased expression of cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) in the sciatic nerve. The results provide new evidence for a role of the endocannabinoid system in pain modulation and point to anandamide transport as a potential target for analgesic drug development.

Journal of Pharmacology and Experimental Therapeutics, March 2006



Arthritis and cannabinoids: HU-210 and Win-55,212-2 prevent IL-1alpha-induced matrix degradation in bovine articular chondrocytes in-vitro

Mbvundula E.C., Bunning R.A., Rainsford K.D.

Biomedical Research Centre, Sheffield Hallam University, Sheffield, S1 1WB, UK.

Cannabinoids have analgesic, immunomodulatory and anti-inflammatory properties and attenuate joint damage in animal models of arthritis. In this study the mechanisms of action of the synthetic cannabinoid agonists, HU-210 and Win-55,212-2, were studied to determine if they affected interleukin-1 alpha (IL-1alpha)-induced proteoglycan and collagen degradation in bovine nasal cartilage explant cultures and prostaglandin E2 (PGE2) production in primary cultures of bovine articular chondrocytes. The effects of the inactive enantiomer, Win-55,212-3, were compared with those of the active enantiomer, Win-55,212-2, to determine if the effects were cannabinoid (CB)-receptor mediated. The chondrocytes and explants were stimulated by IL-1alpha (100 U mL(-1) identical with 0.06 nM and 500 U mL(-1) identical with 0.3 nM, respectively). Proteoglycan breakdown was determined as sulfated glycosaminoglycan (sGAG) release using the dimethylmethylene blue assay. Collagen degradation was determined as hydroxyproline in the conditioned culture media and cartilage digests. PGE2 was determined by ELISA. Expression of cannabinoid receptors, CB1 and CB2; cyclooxygenase-1 and -2 (COX-1 and COX-2); inducible nitric oxide synthase (iNOS); as well as activation of nuclear factor-kappa B (NF-kappaB) in chondrocytes were studied using immunoblotting techniques and immunofluorescence. The results showed that HU-210 and Win-55,212-2 (5-15 microM) significantly inhibited IL-1-alpha stimulated proteoglycan (P < 0.001) and collagen degradation (P < 0.001). Win-55,212-2 (5-10 microM) also significantly inhibited PGE2 production (P < 0.01). At 5 microM, Win-55,212-2 inhibited the expression of iNOS and COX-2 and activation of NF-kappaB. Chondrocytes appeared to constitutively express cannabinoid receptors CB1 and CB2. It is concluded that biologically stable synthetic cannabinoids protect cartilage matrix from degradation induced by cytokines and this effect is possibly CB-receptor mediated and involves effects on prostaglandin and nitric oxide metabolism. Cannabinoids could also be producing these effects via inhibition of NF-kappaB activation.

The Journal of Pharmacy and Pharmacology, March 2006



CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids

Mohab M. Ibrahim *, Frank Porreca *,+, Josephine Lai +, Phillip J. Albrecht ++, Frank L. Rice ++, Alla Khodorova +++, Gudarz Davar , Alexandros Makriyannis ||, Todd W. Vanderah +, Heriberto P. Mata *, and T. Philip Malan, Jr. *,+

*Department of Anesthesiology, University of Arizona College of Medicine, Tucson, AZ; +Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ;++ Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY; +++Pain Research Center, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA; Amgen, Inc., Thousand Oaks, CA; and ||Center for Drug Discovery, Departments of Medicinal Chemistry and Molecular and Cell Biology, University of Connecticut, Storrs, CT

CB2 cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB2 receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB2 receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB2 receptor-mediated inhibition of pain responses. Here, we test the hypothesis that CB2 receptor activation stimulates release from keratinocytes of the endogenous opioid β-endorphin, which then acts at opioid receptors on primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB2 receptor-selective agonist AM1241 were prevented in rats when naloxone or antiserum to β-endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, suggesting that β-endorphin is necessary for CB2 receptor-mediated antinociception. Further, AM1241 did not inhibit nociception in µ-opioid receptor-deficient mice. Hindpaw injection of β-endorphin was sufficient to produce antinociception. AM1241 stimulated β-endorphin release from rat skin tissue and from cultured human keratinocytes. This stimulation was prevented by AM630, a CB2 cannabinoid receptor-selective antagonist and was not observed in skin from CB2 cannabinoid receptor-deficient mice. These data suggest that CB2 receptor activation stimulates release from keratinocytes of β-endorphin, which acts at local neuronal µ-opioid receptors to inhibit nociception. Supporting this possibility, CB2 immunolabeling was detected on β-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of β-endorphin, where CB2 receptors are present, leading to anatomical specificity of opioid effects.

Proceedings of the National Academy of Science, February 2005



The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis

Daniela Cota1, Giovanni Marsicano2, Matthias Tschöp3, Yvonne Grübler1, Cornelia Flachskamm4, Mirjam Schubert5, Dorothee Auer5, Alexander Yassouridis6, Christa Thöne-Reineke7, Sylvia Ortmann8, Federica Tomassoni9, Cristina Cervino9, Enzo Nisoli10, Astrid C.E. Linthorst4, Renato Pasquali9, Beat Lutz2, Günter K. Stalla1 and Uberto Pagotto9

1Clinical Neuroendocrinology Group and; 2Molecular Genetics of Behavior Group, Max-Planck-Institute of Psychiatry, Munich, Germany; 3Department of Pharmacology, German Institute of Human Nutrition, Bergholz-Rehbrücke, Germany; 4Neurochemistry Group; 5Magnetic Resonance Imaging and Spectroscopy Group ;6Biostatistics Group, Max-Planck-Institute of Psychiatry, Munich, Germany; 7Max-Rubner-Laboratory, German Institute of Human Nutrition, Bergholz-Rehbrücke, Germany; 8Institute for Zoo and Wildlife Research, Berlin, Germany; 9Endocrinology Unit and Centro di Ricerca Biomedica Applicata, Sant Orsola-Malpighi Hospital, Bologna, Italy; 10Center for Study and Research on Obesity, Department of Preclinical Sciences, School of Medicine, University of Milan, Laboratori Interdisciplinari di Tecnologie Avanzate Vialba, Luigi Sacco Hospital, Milan, Italy

The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1−/−) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1−/−mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1−/− mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and prepro-orexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1−/− mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.

Journal of Clinical Investigation, April 2003.



The Emerging Role of the Endocannabinoid System in Endocrine Regulation and Energy Balance

Uberto Pagotto, Giovanni Marsicano, Daniela Cota, Beat Lutz and Renato Pasquali

Endocrinology Unit, Department of Internal Medicine and Gastroenterology, and Center for Applied Biomedical Research (U.P., R.P.), Sant. Orsola-Malpighi Hospital, 40138 Bologna, Italy; Department of Physiological Chemistry (G.M., B.L.), Johannes Gutenberg-University Mainz, 55099 Mainz, Germany; and University of Cincinnati, Department of Psychiatry, Obesity Research Center, Genome Research Institute (D.C.), Cincinnati, Ohio 45237

During the last few years, the endocannabinoid system has emerged as a highly relevant topic in the scientific community. Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors, named CB1 receptor and CB2 receptor, first discovered as the molecular targets of the psychotropic component of the plant Cannabis sativa, participate in the physiological modulation of many central and peripheral functions. CB2 receptor is mainly expressed in immune cells, whereas CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain. CB1 receptor is expressed in the hypothalamus and the pituitary gland, and its activation is known to modulate all the endocrine hypothalamic-peripheral endocrine axes. An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior. The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the gastrointestinal tract, and, possibly, skeletal muscle. The relevance of the system is further strenghtened by the notion that drugs interfering with the activity of the endocannabinoid system are considered as promising candidates for the treatment of various diseases, including obesity.

The Endocrine Society, February 2006



Cannabinoid receptor-mediated regulation of intracellular calcium by Δ9-tetrahydrocannabinol in resting T cells

Gautham K. Rao*, Wei Zhang*, and Norbert E. Kaminski*,

* Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, and Center for Integrative Toxicology, Michigan State University, East Lansing

Cannabinoids exhibit broad immune modulating activity by targeting many cell types within the immune system, including T cells, which exhibit sensitivity, as evidenced by altered activation, proliferation, and cytokine expression. As a result of the critical role calcium plays in T cell function coupled with previous findings demonstrating disruption of the calcium-regulated transcription factor, nuclear factor of activated T cells, by cannabinoid treatment, the objective of the present investigation was to perform an initial characterization of the role of the cannabinoid receptors in the regulation of the intracellular calcium concentration ([Ca2+]i) by Δ9-tetrahydrocannabinol (Δ9-THC) in T lymphocytes. Here, we demonstrate that Δ9-THC robustly elevates [Ca2+]i in purified murine splenic T cells and in the human peripheral blood acute lymphoid leukemia (HPB-ALL) human T cell line but only minimally elevates [Ca2+]i in Jurkat E6-1 (dysfunctional cannabinoid receptor 2-expressing) human T cells. Removal of extracellular calcium severely attenuated the Δ9-THC-mediated rise in [Ca2+]i in murine splenic T cells and HPB-ALL cells. Pretreatment with cannabinoid receptor antagonists, SR144528 and/or SR141716A, led to an attenuation of Δ9-THC-mediated elevation in [Ca2+]i in splenic T cells and HPB-ALL cells but not in Jurkat E6-1 cells. Furthermore, pretreatment of HPB-ALL cells with SR144528 antagonized the small rise in [Ca2+]i elicited by Δ9-THC in the absence of extracellular calcium. These findings suggest that Δ9-THC induces an influx of extracellular calcium in resting T cells in a cannabinoid receptor-dependent manner.

Journal of Leukocyte Biology, February 2004



The effects of cannabinoids on contextual conditioned fear in CB1 knockout and CD1 mice

Mikics E., Dombi T., Barsvari B., Varga B., Ledent C., Freund T.F., Haller J.

Institute of Experimental Medicine, Budapest, Hungary bIRIBHM, Free University of Brussels, Brussels, Belgium.

We studied the effects of cannabinoids on contextual conditioned fear responses. CB1 knockout and wild-type (CD1) mice were exposed to a brief session of electric shocks, and their behavior was studied in the same context 24 h later. In wild-type mice, shock exposure increased freezing and resting, and decreased locomotion and exploration. The genetic disruption of the CB1 receptor abolished the conditioned fear response. The CB1 antagonist AM-251 reduced the peak of the conditioned fear response when applied 30 min before behavioral testing (i.e. 24 h after shocks) in CD1 (wild-type) mice. The cannabinoid agonist WIN-55,212-2 markedly increased the conditioned fear response in CD1 mice, the effect of which was potently antagonized by AM-251. Thus, cannabinoid receptor activation appears to strongly promote the expression of contextual conditioned fear. In earlier experiments, cannabinoids did not interfere with the expression of cue-induced conditioned fear but strongly promoted its extinction. Considering the primordial role of the amygdala in simple associative learning (e.g. in cue-induced fear) and the role of the hippocampus in learning more complex stimulus relationships (e.g. in contextual fear), the present and earlier findings are not necessarily contradictory, but suggest that cannabinoid signaling plays different roles in the two structures. Data are interpreted in terms of the potential involvement of cannabinoids in trauma-induced behavioral changes.

Behavioural Pharmacology, April 2006



Cannabinoids and glaucoma

I. Tomida1, R.G. Pertwee2 and A. Azuara-Blanco1

1 Department of Ophthalmology, Aberdeen Royal Infirmary, University of Aberdeen, UK 2 Department of Biomedical Sciences, Institute of Medical Sciences, 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.

British Journal of Ophthalmology, October 2003



The Endocannabinoid System Promotes Astroglial Differentiation by Acting on Neural Progenitor Cells

Tania Aguado1, Javier Palazuelos1,, Krisztina Monory,2, Nephi Stella3, Benjamin Cravatt4, Beat Lutz2, Giovanni Marsicano2, Zaal Kokaia5, Manuel Guzmán1, and Ismael Galve-Roperh1.

1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain, 2Max-Planck Institute of Psychiatry, 80804 Munich, Germany, 3Department of Pharmacology, Washington University, Seattle, Washington 98195, 4The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, and 5Laboratory of Neural Stem Cell Biology, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, University Hospital, SE-221 84 Lund, Sweden

Endocannabinoids exert an important neuromodulatory role via presynaptic cannabinoid CB1 receptors and may also participate in the control of neural cell death and survival. The function of the endocannabinoid system has been extensively studied in differentiated neurons, but its potential role in neural progenitor cells remains to be elucidated. Here we show that the CB1 receptor and the endocannabinoid-inactivating enzyme fatty acid amide hydrolase are expressed, both in vitro and in vivo, in postnatal radial glia (RC2+ cells) and in adult nestin type I (nestin+GFAP+) neural progenitor cells. Cell culture experiments show that CB1 receptor activation increases progenitor proliferation and differentiation into astroglial cells in vitro. In vivo analysis evidences that, in postnatal CB1−/− mouse brain, progenitor proliferation and astrogliogenesis are impaired. Likewise, in adult CB1-deficient mice, neural progenitor proliferation is decreased but is increased in fatty acid amide hydrolase-deficient mice. In addition, endocannabinoid signaling controls neural progenitor differentiation in the adult brain by promoting astroglial differentiation of newly born cells. These results show a novel physiological role of endocannabinoids, which constitute a new family of signaling cues involved in the regulation of neural progenitor cell function.

Journal of Neruoscience, February 2006



Depressive symptoms lead to impaired cellular immune response

Fortes C., Farchi S., Forastiere F., Agabiti N., Pacifici R., Zuccaro P., Perucci C.A.,

Clinical Epidemiology Unit, IDI-IRCSS, Rome, Italy

The association between depression and immune response is not yet clear. The biological mechanism by which depression alters the immune system is not yet understood. (In One study,) 166 elderly people were tracked for four years,( blood tests were included in the study.) They found that depression affected the immune system adversely.

Psychotherapy Psychosom., September 2003



The relationship between chronic pain, immune function, depression, and health behaviors

Vines S.W., Gupta S., Whiteside T., Dostal-Johnson D., Hummler-Davis A.

College of Nursing and Health Professions, University of Southern Maine, USA. swvines@earthlink.net

Researchers found that even chronic pain was detrimental to immune function as well. By comparing a group of pain free people against chronic pain sufferers, depression and health behaviors, it showed that chronic pain patients' immune function, as measured by the combined NK effector to target (E:T) cell ratio levels, was significantly higher than the no-pain comparison group.

Biol Res Nurs. 2003 Jul



Psychoneuroimmunology and the faith factor

Koenig H.G.

Duke University Medical Center and GRECC, Veterans Administration Medical Center, Durham, NC, USA

Good mental health has been linked with better immune function. Psychoneuroimmunology (PNI), describes the physiological mechanisms by which the mind affects the body. Scientists reviewed research substantiating the link between psychosocial processes and immune functioning

Gender Specific Medicine, Jul-Aug 2000



The course of functional decline in older people with persistently elevated depressive symptoms: longitudinal findings from the Cardiovascular Health Study

Lenze E.J., Schulz R., Martire L.M., Zdaniuk B., Glass T., Kop W.J., Jackson S.A., Reynolds C.F.

Intervention Research Center in Late-Life Mood Disorders, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

In a study of 5,888 people, researchers found that persistently elevated depressive symptoms in elderly persons are associated with a steep trajectory of worsening functional disability.

Geriatric Society, April 2005



Depressive symptoms and development of coronary heart disease events: the Italian longitudinal study on aging

Marzari C., Maggi S., Manzato E., Destro C., Noale M., Bianchi D., Minicuci N., Farchi G., Baldereschi M., Di Carlo A., Crepaldi G.

National Research Council, Aging Branch, Institute of Neuroscience, Padova, Italy

Depressive symptomatology confers an increased risk for CHD(Coronary Heart disease) in men and for total mortality in men and women but is not explained by health behaviors, social isolation, or biological or clinical determinants a study of 5632 people.

8 J Gerontol A Biol Sci Med Sci. 2005 Jan;60(1):85-92.



Update on drug-induced depression in the elderly

Kotlyar M., Dysken M., Adson D.E.

Depression is common in elderly people (and those affected by a terminal or debilitating illness). Some drugs may cause new onset depression or worsen established depression. (Pharmaceutical) drugs like anti hyper tensives, lipid lowering modulators, and estrogen receptor modulators,

Geriatric Pharmacotherapy 2005 Dec;3(4):288-300 2006
Associated study:
[Hepatitis C., Interferon A and depression: Main physiopathologic hypothesis].

Vignau J., Karila L., Costisella O., Canva V.


A therapeutic role for cannabinoid CB1 receptor antagonists in major depressive disorders

Witkin J.M., Tzavara E.T., Davis R.J., Li X., Nomikos G.G.

Psychiatric Drug Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0510, USA. jwitkin@lilly.com

Cannabinoid receptors in the CNS have been implicated in the control of appetite, cognition, mood and drug dependence. Recent findings support the hypothesis that cannabinoid CB1 receptor blockade might be associated with antidepressant and anti-stress effects. A novel potential antidepressant drug class based on this mechanism is supported by the neuroanatomical localization of CB1 receptors and signal transduction pathways that are involved in emotional responses, together with the antidepressant-like neurochemical and behavioral effects induced by CB1 receptor antagonists. Selective CB1 receptor antagonists are in development for the treatment of obesity and tobacco smoking, and could be tested for antidepressant efficacy because recent results of clinical studies suggest that they would also treat comorbid symptoms of depression such as cognitive deficiencies, weight gain, impulsivity and dependence disorders. Thus, CB1 receptor antagonism might constitute an integrated pharmacotherapeutic approach that impacts the affective, cognitive, appetitive and motivational neuronal networks involved in mood disorders.

Trends in Pharmacological Sciences, November 2005



Decreased depression in marijuana users

Thomas F. Densonaa, and Mitchell Earleywineb.

aUniversity of Southern California, Seeley G. Mudd Building, Room 501, Los Angeles, CA, 90089-1061, United States, bUniversity at Albany, State University of New York, United States

Over 4400 adult internet users completed The Center for Epidemiologic Studies Depression scale and measures of marijuana use. We employed an internet survey in an effort to recruit the most depressed and marijuana-involved participants, including those who might prove unwilling to travel to the laboratory or discuss drug use on the phone or in person. We compared those who consumed marijuana daily, once a week or less, or never in their lives. Despite comparable ranges of scores on all depression subscales, those who used once per week or less had less depressed mood, more positive affect, and fewer somatic complaints than non-users. Daily users reported less depressed mood and more positive affect than non-users. The three groups did not differ on interpersonal symptoms. Separate analyses for medical vs. recreational users demonstrated that medical users reported more depressed mood and more somatic complaints than recreational users, suggesting that medical conditions clearly contribute to depression scores and should be considered in studies of marijuana and depression. These data suggest that adults apparently do not increase their risk for depression by using marijuana.

Addictive Behaviors, June 2005



Current evidence does not show a strong causal relation between the use of cannabis in young people and psychosocial harm

Macleod J., Oakes R., Copello A., et al.

UK Department of Health, Drug Misuse Research Initiative

MAIN RESULTS: Sixteen out of 48 longitudinal studies were classified as of higher methodological quality. Cannabis use was consistently associated with reduced educational attainment and use of other drugs. However, when estimates were adjusted for potential confounding factors, these estimates were often substantially attenuated. Cannabis use was inconsistently associated with psychological problems and antisocial or problematic behaviour; however, adjustment of these estimates generally led to their attenuation, often substantially so.
CONCLUSIONS: Using existing evidence, no causal relation can be shown between cannabis use by young people and psychosocial harm.

Lancet 2004;363:1579.88



Cannabinoids in bipolar affective disorder: A review and discussion of their therapeutic potential

Ashton C.H.; Moore P.B.; Gallagher P.; Young A.H.

Department of Psychiatry, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, UK

Bipolar affective disorder is often poorly controlled by prescribed drugs. Cannabis use is common in patients with this disorder and anecdotal reports suggest that some patients take it to alleviate symptoms of both mania and depression. We undertook a literature review of cannabis use by patients with bipolar disorder and of the neuropharmacological properties of cannabinoids suggesting possible therapeutic effects in this condition. No systematic studies of cannabinoids in bipolar disorder were found to exist, although some patients claim that cannabisrelieves symptoms of mania and/or depression. The cannabinoids Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) may exert sedative, hypnotic, anxiolytic, antidepressant, antipsychotic and anticonvulsant effects. Pure synthetic cannabinoids, such as dronabinol and nabilone and specific plant extracts containing THC, CBD, or amixture of the two in known concentrations, are available and can be delivered sublingually. Controlled trials of these cannabinoids as adjunctive medication in bipolar disorder are now indicated.

Journal of Psychopharmacology 19(3): 293-300, 2005



Cannabis, Mental Health and Context: The Case For Regulation

Paul Armentano

Senior Policy Analyst NORML | NORML Foundation

A recent clinical study published in the April 2005 issue of the journal Psychiatry Research refuting a causal link between cannabis use and behavior suggestive of schizophrenia. "The current study ... suggest[s] a temporal precedence of schizotypal traits before cannabis use in most cases," its authors concluded. "These findings do not support a causal link between cannabis use and schizotypal traits."2 Survey data published in the journal Addictive Behavior also puts a damper on the White House's "pot leads to depression" claims. After analyzing survey results from 4,400 adults who had completed The Center for Epidemiologic Studies Depression scale (a numerical, self-report scale designed to assess symptoms of depression in the general population), researchers at the University of Southern California found: "Despite comparable ranges of scores on all depression subscales, those who used once per week or less had less depressed mood, more positive affect, and fewer somatic (physical) complaints than non-users. ... Daily users [also] reported less depressed mood and more positive affect than non-users." Lastly, there are the results of a recent meta-analysis published in the journal Current Opinion in Pharmacology. The study's verdict? Those who use cannabis in moderation, even long-term "will not suffer any lasting physical or mental harm.

2 J Schiffman et al. 2005. Symptoms of schizotypy precede cannabis use. Psychiatric Research 134: 37-42.

Important references mentioned in the full text:
4 Leslie Iverson. 2005. Long-term effects of exposure to cannabis. Current Opinion in Pharmacology 5: 69-72.

5 The British Advisory Council on the Misuse of Drugs noted, "On current evidence, smoking cannabis was likely to increase the chances of developing schizophrenia by just one percent". London Telegraph. "Cannabis use will impair but not damage mental health". January 23, 2006.

6 D Fergusson et al. 2006. Cannabis and psychosis. British Medical Journal 332: 172-175; Wayne Hall. 2006. The mental health risks of adolescent cannabis use. PLOS Medicine 3; D Semple et al. 2005. Cannabis as a risk factor for psychosis: systemic review. Journal of Psychopharmacology 19: 187-194.

7 R Ferdinand et al. 2005. Cannabis use predicts future psychotic symptoms, and vice versa. Addiction 100: 612-618.



Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia

Walther S., Mahlberg R., Eichmann U., Kunz D.

Department of Psychiatry and Psychotherapy, Charite Universitatsmedizin Berlin, Campus Charite Mitte (PUK), Berlin, Germany.

RATIONALE: Nighttime agitation occurs frequently in patients with dementia and represents the number one burden on caregivers today. Current treatment options are few and limited due to substantial side effects. OBJECTIVES: The aim of the study was to measure the effect of the cannabinoid dronabinol on nocturnal motor activity. METHODS: In an open-label pilot study, six consecutive patients in the late stages of dementia and suffering from circadian and behavioral disturbances-five patients with Alzheimer's disease and one patient with vascular dementia-were treated with 2.5 mg dronabinol daily for 2 weeks. Motor activity was measured objectively using actigraphy.
RESULTS: Compared to baseline, dronabinol led to a reduction in nocturnal motor activity (P=0-028). These findings were corroborated by improvements in Neuropsychiatric Inventory total score (P=0-027) as well as in subscores for agitation, aberrant motor, and nighttime behaviors (P<0-05). No side effects were observed.
CONCLUSIONS: The study suggests that dronabinol was able to reduce nocturnal motor activity and agitation in severely demented patients. Thus, it appears that dronabinol may be a safe new treatment option for behavioral and circadian disturbances in dementia.

Psychopharmacology, March 2006



Cannabinoid Receptor as a Novel Target for the Treatment of Prostate Cancer

Sami Sarfaraz, Farrukh Afaq, Vaqar M. Adhami and Hasan Mukhtar

Department of Dermatology, University of Wisconsin, Madison, Wisconsin

Cannabinoids, the active components of Cannabis sativa Linnaeus (marijuana) and their derivatives have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects and tumor regression. Here we show that expression levels of both cannabinoid receptors, CB1 and CB2 , are significantly higher in CA-human papillomavirus-10 (virally transformed cells derived from adenocarcinoma of human prostate tissue), and other human prostate cells LNCaP, DUI45, PC3, and CWR22Rν 1 than in human prostate epithelial and PZ-HPV-7 (virally transformed cells derived from normal human prostate tissue) cells. WIN-55,212-2 (mixed CB1 /CB2 agonist) treatment with androgen-responsive LNCaP cells resulted in a dose- (1-10 µmol/L) and time-dependent (24-48 hours) inhibition of cell growth, blocking of CB1 and CB2 receptors by their antagonists SR141716 (CB1) and SR144528 (CB2) significantly prevented this effect. Extending this observation, we found that WIN-55,212-2 treatment with LNCaP resulted in a dose- (1-10 µmol/L) and time-dependent (24-72 hours) induction of apoptosis (a), decrease in protein and mRNA expression of androgen receptor (b), decrease in intracellular protein and mRNA expression of prostate-specific antigen (c), decrease in secreted prostate-specific antigen levels (d), and decrease in protein expression of proliferation cell nuclear antigen and vascular endothelial growth factor (e). Our results suggest that WIN-55,212-2 or other non.habit-forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer.

American Association for Cancer Research, March 2005



Cristina Blázquez1, Luis González-Feria4, Luis Álvarez2, Amador Haro1, M. Llanos Casanova3 and Manuel Guzmán1

1 Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University; 2 Research Unit, La Paz University Hospital; 3 Project on Cellular and Molecular Biology and Gene Therapy, CIEMAT, Madrid, Spain; and 4 Department of Neurosurgery, University Hospital, Tenerife, Spain

Cannabinoids inhibit tumor angiogenesis in mice, but the mechanism of their antiangiogenic action is still unknown. Because the vascular endothelial growth factor (VEGF) pathway plays a critical role in tumor angiogenesis, here we studied whether cannabinoids affect it. As a first approach, cDNA array analysis showed that cannabinoid administration to mice bearing s.c. gliomas lowered the expression of various VEGF pathway-related genes. The use of other methods (ELISA, Western blotting, and confocal microscopy) provided additional evidence that cannabinoids depressed the VEGF pathway by decreasing the production of VEGF and the activation of VEGF receptor (VEGFR)-2, the most prominent VEGF receptor, in cultured glioma cells and in mouse gliomas. Cannabinoid-induced inhibition of VEGF production and VEGFR-2 activation was abrogated both in vitro and in vivo by pharmacological blockade of ceramide biosynthesis. These changes in the VEGF pathway were paralleled by changes in tumor size. Moreover, intratumoral administration of the cannabinoid Δ9-tetrahydrocannabinol to two patients with glioblastoma multiforme (grade IV astrocytoma) decreased VEGF levels and VEGFR-2 activation in the tumors. Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies.

American Association for Cancer Research, August 2004



Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors

M. Llanos Casanova1, Cristina Blázquez2, Jesús Martínez-Palacio1, Concepción Villanueva3, M. Jesús Fernández-Aceńero3, John W. Huffman4, José L. Jorcano1 and Manuel Guzmán2

1 Project on Cellular and Molecular Biology and Gene Therapy, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain 2 Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain 3 Department of Pathology, Hospital General de Móstoles, Madrid, Spain 4 Department of Chemistry, Clemson University, Clemson, South Carolina, USA

Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB1 and CB2), we studied the potential utility of these compounds in anti-skin tumor therapy. Here we show that the CB1 and the CB2 receptor are expressed in normal skin and skin tumors of mice and humans. In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB1/CB2 agonist WIN-55,212-2 or the selective CB2 agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors.

Journal of Clinical Investigation, November 2002



Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway

Thomas Powles, Robert te Poele, Jonathan Shamash, Tracy Chaplin, David Propper, Simon Joel, Tim Oliver, and Wai Man Liu

From the New Drug Study Group, St Bartholomew's Hospital (SBH), London, United Kingdom; the Department of Medical Oncology, SBH, London, United Kingdom; the Centre for Cancer Therapeutics, Institute of Cancer Research, Surrey, United Kingdom; the Department of Medical Oncology, Charterhouse Square, London, United Kingdom; and the Barry Reed Oncology Laboratory, SBH, London, United Kingdom.

&3916;9-Tetrahydrocannabinol (THC) is the active metabolite of cannabis. THC causes cell death in vitro through the activation of complex signal transduction pathways. However, the role that the cannabinoid 1 and 2 receptors (CB1-R and CB2-R) play in this process is less clear. We therefore investigated the role of the CB-Rs in mediating apoptosis in 3 leukemic cell lines and performed microarray and immunoblot analyses to establish further the mechanism of cell death. We developed a novel flow cytometric technique of measuring the expression of functional receptors and used combinations of selective CB1-R and CB2-R antagonists and agonists to determine their individual roles in this process. We have shown that THC is a potent inducer of apoptosis, even at 1 x IC50 (inhibitory concentration 50%) concentrations and as early as 6 hours after exposure to the drug. These effects were seen in leukemic cell lines (CEM, HEL-92, and HL60) as well as in peripheral blood mononuclear cells. Additionally, THC did not appear to act synergistically with cytotoxic agents such as cisplatin. One of the most intriguing findings was that THC-induced cell death was preceded by significant changes in the expression of genes involved in the mitogen-activated protein kinase (MAPK) signal transduction pathways. Both apoptosis and gene expression changes were altered independent of p53 and the CB-Rs.

Journal of the American Society of Hematology, February 2005



The endogenous cannabinoid system protects against colonic inflammation

Federico Massa1,2, Giovanni Marsicano1, Heike Hermann1, Astrid Cannich1, Krisztina Monory1, Benjamin F. Cravatt3, Gian-Luca Ferri2, Andrei Sibaev4, Martin Storr4 and Beat Lutz1

1Group Molecular Genetics of Behaviour, Max Planck Institute of Psychiatry, Munich, Germany. 2Neuro-Endocrine Fluorescence Laboratory, Department of Cytomorphology, University of Cagliari, Cagliari, Italy. 3Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA. 4II Medical Department, Klinikum Grosshadern, Ludwig Maximilians University of Munich, Munich, Germany.

Excessive inflammatory responses can emerge as a potential danger for organisms' health. Physiological balance between pro- and anti-inflammatory processes constitutes an important feature of responses against harmful events. Here, we show that cannabinoid receptors type 1 (CB1) mediate intrinsic protective signals that counteract proinflammatory responses. Both intrarectal infusion of 2,4 dinitrobenzene sulfonic acid (DNBS) and oral administration of dextrane sulfate sodium induced stronger inflammation in CB1-deficient mice (CB1−/−.) than in wild-type littermates (CB1+/+). Treatment of wild-type mice with the specific CB1 antagonist N-(piperidino-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide (SR141716A) mimicked the phenotype of CB1−/− mice, showing an acute requirement of CB1 receptors for protection from inflammation. Consistently, treatment with the cannabinoid receptor agonist R(-)-7-hydroxy- Δ6-tetra-hydrocannabinol-dimethylheptyl (HU210) or genetic ablation of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) resulted in protection against DNBS-induced colitis. Electrophysiological recordings from circular smooth muscle cells, performed 8 hours after DNBS treatment, revealed spontaneous oscillatory action potentials in CB1−/− but not in CB1+/+ colons, indicating an early CB1-mediated control of inflammation-induced irritation of smooth muscle cells. DNBS treatment increased the percentage of myenteric neurons expressing CB1 receptors, suggesting an enhancement of cannabinoid signaling during colitis. Our results indicate that the endogenous cannabinoid system represents a promising therapeutic target for the treatment of intestinal disease conditions characterized by excessive inflammatory responses.

Journal of Clinical Investigation, April 2004



Cannabinoids inhibit neurodegeneration in models of multiple sclerosis

Gareth Pryce*,1, Zubair Ahmed*,1, Deborah J. R. Hankey*,1, Samuel J. Jackson1, J. Ludovic Croxford1, Jennifer M. Pocock1, Catherine Ledent2, Axel Petzold1, Alan J. Thompson3, Gavin Giovannoni1, M. Louise Cuzner1 and David Baker1

1 Department of Neuroinflammation, Institute of Neurology, University College London, London, UK, 2 Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Universite libre de Bruxelles, Brussels, Belgium and 3 Neurorehabilitation Group, Institute of Neurology, University College London, Queen Square, London, UK. *These authors contributed equally to this work

Multiple sclerosis is increasingly being recognized as a neurodegenerative disease that is triggered by inflammatory attack of the CNS. As yet there is no satisfactory treatment. Using experimental allergic encephalo myelitis (EAE), an animal model of multiple sclerosis, we demonstrate that the cannabinoid system is neuroprotective during EAE. Mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excito toxic insults poorly and develop substantial neurodegeneration following immune attack in EAE. In addition, exogenous CB1 agonists can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental allergic uveitis model. Therefore, in addition to symptom management, cannabis may also slow the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably other diseases.

Brain, A Journal of Neurology, October 2003



Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R(+)WIN55,212

J. Ludovic Croxford and Stephen D. Miller

Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, Illinois, USA

Theiler murine encephalomyelitis virus.induced demyelinating disease (TMEV-IDD) is a mouse model of chronic-progressive multiple sclerosis (MS) characterized by Th1-mediated CNS demyelination and spastic hindlimb paralysis. Existing MS therapies reduce relapse rates in 30% of relapsing-remitting MS patients, but are ineffective in chronic-progressive disease, and their effects on disability progression are unclear. Experimental studies demonstrate cannabinoids are useful for symptomatic treatment of spasticity and tremor in chronic-relapsing experimental autoimmune encephalomyelitis. Cannabinoids, however, have reported immunosuppressive properties. We show that the cannabinoid receptor agonist, R(+)WIN55,212, ameliorates progression of clinical disease symptoms in mice with preexisting TMEV-IDD. Amelioration of clinical disease is associated with downregulation of both virus and myelin epitope-specific Th1 effector functions (delayed-type hypersensitivity and IFN- γ production) and the inhibition of CNS mRNA expression coding for the proinflammatory cytokines, TNF-α, IL1-ß, and IL-6. Clinical trials investigating the therapeutic potential of cannabinoids for the symptomatic treatment of MS are ongoing, and this study demonstrates that they may also have potent immunoregulatory properties.

Journal of Clinical Investigation, February 2003