Israel’s leading Contract and
Clinical Research Organization (CRO)
dedicated to the study of medical cannabis.

 A traditional CRO, in an ever-evolving world.

 

Discover endoCRO

Cannabis is revolutionizing the face of traditional modern medicine as we know it! Evidence-based research is the key to advancing our knowledge of the vast medical properties of this complex plant. EndoCRO provides the world’s most established and highly-developed cannabis R&D resources -from genetics to pharma- in order to discover the true potential of cannabis as a legitimate treatment option for patients worldwide.

 

We are a full service CRO, committed to advancing the study and application of cannabis by bringing it out of the realm of speculation and into evidence-based medicine.

 
MEDICAL CANNABIS IS
EXPECTED TO GROW FROM
$2.9BILLION
industry TODAY

$7.6  BILLION
industry by 
2020
TO

WHY ISRAEL

Reputation & Experience

Israel was among the world’s earliest adopters of a legal medical cannabis program and as such is recognized as the global leader in the study of the cannabis plant. Either as a stand-alone or as part of a multi-center approach, we can implement clinical trials complying with International Standards including ICH GCP, The Clinical Trial Directive 2001/20/EU and the code of Federal Regulations (FDA 21 CFR).

Culture of Integrity

We are leaders in both research and clinical study of cannabis medicine and are unparalleled in our global understanding and application of every part of the medical cannabis chain.

World Class Specialist
Working with leading Principal Investigators and their teams, EndoCRO has a professional network of physicians in four of the largest hospitals in Israel. These centers have all participated in multi-site, multinational, GCP studies. Additionally, we offer multi-center studies in Israel, Canada, Australia and the United States.
Quality Management

Quality processes are embedded in EndoCRO’s delivery model. Our dedicated Quality Assurance Manager supports each project team to ensure that all processes are established and meet regulatory requirements and protocol.

 

APPROVAL PROCESS

1 Month
1 - 3 Months
1 Month

For a Clinical Study in Israel

(Helsinki Commitee)

Study Documentation            Document Required

Study Request Form                                                   Form 1a

Protocol                                                                       Yes

Investigator’s Brochure                                              Yes

Relevant LIterature                                                     Yes

Informed Consent Form                                              Form 2a or 3a

Sponsor Liability Form                                               Form 4a 

Sponsor Declaration Form                                         Form 5

Health Fund Form                                                       Form 11

Checklist                                                                      Form 9

Recruitment Advertising                                            Form 10

​(If Appicable) 

NO
YES
Ministry of Health
- Clinical Trials Division
- Experts Division
- Central Commitee
- Supreme Commitee

CRO SERVICES

  • Formulation, delivery systems 

  • Pre-clinical and clinical study design and protocol development

  • Construction of project budget

  • CRF development

  • Regulatory submissions 

  • Site selection process

  • Site monitoring activities

Regulatory Compliance
 

Working with the Israeli Ministry of Health, endoCRO and our partner network have gained experience in preparing for and conducting clinical investigations. Compliant with International Standards including ICH, GCP, The Clinical Trial Directive 2001/20/EU and the code of Federal Regulations (FDA 21 CFR).

Site Management

Working with leading Principal Investigators and their teams, endoCRO has a professional network of physicians in four of the largest hospitals in Israel. These centers have all participated in multi-site, multinational, GCP studies, and due to the regulatory status and history of approvals, the study of medical cannabis is often much faster in Israel than in other countries.

Investigational Products
 

endoCRO is proud of its close ties with some of Israel’s most experienced growers, formulators and manufacturers, and can supply the investigational product in adherence to the study protocol, GMP and local regulations. endoCRO is able to work with a local team to provide storage and transportation in compliance with local regulations.

 
 
CLINICAL INVESTIGATIONS
A deep and broad history

For over 50 years, Israel has led the world in medical cannabis research spearheaded by the groundbreaking work of Professor Raphael Mechoulam from Hadassah Medical Center in Jerusalem.

In 1963, Mechoulam and his research partners revealed the structure of cannabidiol (CBD), a key ingredient in cannabis and the following year they had isolated THC for the first time, established its structure and synthesized it. The research has since continued. Below is a snapshot of some of the research performed by Israeli institutions:

Human Clinical Trials

Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study

Yeshurun, Moshe; Shpilberg, Ofer; Herscovici, Corina; Shargian, Liat; Dreyer, Juliet; Peck, Anat; Israeli, Moshe; Levy-Assaraf, Maly; Gruenewald, Tsipora; Mechoulam, Raphael; Raanani, Pia; Ram, Ron

Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel.

Tissue Typing Laboratory, Rabin Medical Center, Petah-Tikva, Israel.

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Pharmacy Services, Rabin Medical Center, Petah-Tikva, Israel.

Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, Israel.

Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation, 2015

http://www.ncbi.nlm.nih.gov/pubmed/26033282

Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. 

CONCLUSION: The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted. (clinicaltrials.gov: NCT01385124).

Cannabis for inflammatory bowel disease

Naftali, Timna; Mechulam, Raphael; Lev, Lihi Bar; Konikoff, Fred M.

Institute of Gastroenterology and Hepatology, Meir Medical Center, Kfar Saba, Israel.

Digestive Diseases, 2014

http://www.ncbi.nlm.nih.gov/pubmed/24969296

The marijuana plant Cannabis sativa has been used for centuries as a treatment for a variety of ailments. It contains over 60 different cannabinoid compounds. Studies have revealed that the endocannabinoid system is involved in almost all major immune events. Cannabinoids may, therefore, be beneficial in inflammatory disorders. In murine colitis, cannabinoids decrease histologic and microscopic inflammation. In humans, cannabis has been used to treat a plethora of gastrointestinal problems, including anorexia, emesis, abdominal pain, diarrhea, and diabetic gastroparesis. Despite anecdotal reports on medical cannabis in inflammatory bowel disease (IBD), there are few controlled studies. In an observational study in 30 patients with Crohn's disease (CD), we found that medical cannabis was associated with improvement in disease activity and reduction in the use of other medications. In a more recent placebo-controlled study in 21 chronic CD patients, we showed a decrease in the CD activity index >100 in 10 of 11 subjects on cannabis compared to 4 of 10 on placebo. Complete remission was achieved in 5 of 11 subjects in the cannabis group and 1 of 10 in the placebo group. Yet, in an additional study, low-dose cannabidiol did not have an effect on CD activity. 

In summary, evidence is gathering that manipulating the endocannabinoid system can have beneficial effects in IBD, but further research is required to declare cannabinoids a medicine. We need to establish the specific cannabinoids, as well as appropriate medical conditions, optimal dose, and mode of administration, to maximize the beneficial effects while avoiding any potential harmful effects of cannabinoid use. 

 

Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study

Lotan, Itay; Treves, Therese A.; Roditi, Yaniv; Djaldetti, Ruth

Department of Neurology, Rabin Medical Center, Beilinson Hospital, Petach Tikva; and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Clinical Neuropharmacology, 2014

http://www.ncbi.nlm.nih.gov/pubmed/24614667

OBJECTIVE: The use of cannabis as a therapeutic agent for various medical conditions has been well documented. However, clinical trials in patients with Parkinson disease (PD) have yielded conflicting results. The aim of the present open-label observational study was to assess the clinical effect of cannabis on motor and non-motor symptoms of PD. METHODS: Twenty-two patients with PD attending the motor disorder clinic of a tertiary medical center in 2011 to 2012 were evaluated at baseline and 30 minutes after smoking cannabis using the following battery: Unified Parkinson Disease Rating Scale, visual analog scale, present pain intensity scale, Short-Form McGill Pain Questionnaire, as well as Medical Cannabis Survey National Drug and Alcohol Research Center Questionnaire. RESULTS: Mean (SD) total score on the motor Unified Parkinson Disease Rating Scale score improved significantly from 33.1 (13.8) at baseline to 23.2 (10.5) after cannabis consumption (t = 5.9; P < 0.001). Analysis of specific motor symptoms revealed significant improvement after treatment in tremor (P < 0.001), rigidity (P = 0.004), and bradykinesia (P < 0.001). 

CONCLUSIONS: There was also significant improvement of sleep and pain scores. No significant adverse effects of the drug were observed. The study suggests that cannabis might have a place in the therapeutic armamentarium of PD. Larger, controlled studies are needed to verify the results.

 

Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study

Lotan, Itay; Treves, Therese A.; Roditi, Yaniv; Djaldetti, Ruth

Department of Neurology, Rabin Medical Center, Beilinson Hospital, Petach Tikva; and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Clinical Neuropharmacology, 2014

http://www.ncbi.nlm.nih.gov/pubmed/24614667

OBJECTIVE: The use of cannabis as a therapeutic agent for various medical conditions has been well documented. However, clinical trials in patients with Parkinson disease (PD) have yielded conflicting results. The aim of the present open-label observational study was to assess the clinical effect of cannabis on motor and non-motor symptoms of PD. METHODS: Twenty-two patients with PD attending the motor disorder clinic of a tertiary medical center in 2011 to 2012 were evaluated at baseline and 30 minutes after smoking cannabis using the following battery: Unified Parkinson Disease Rating Scale, visual analog scale, present pain intensity scale, Short-Form McGill Pain Questionnaire, as well as Medical Cannabis Survey National Drug and Alcohol Research Center Questionnaire. RESULTS: Mean (SD) total score on the motor Unified Parkinson Disease Rating Scale score improved significantly from 33.1 (13.8) at baseline to 23.2 (10.5) after cannabis consumption (t = 5.9; P < 0.001). Analysis of specific motor symptoms revealed significant improvement after treatment in tremor (P < 0.001), rigidity (P = 0.004), and bradykinesia (P < 0.001).

CONCLUSIONS: There was also significant improvement of sleep and pain scores. No significant adverse effects of the drug were observed. The study suggests that cannabis might have a place in the therapeutic armamentarium of PD. Larger, controlled studies are needed to verify the results.

Impact of cannabis treatment on the quality of life, weight and clinical disease activity in inflammatory bowel disease patients: a pilot prospective study

Lahat, Adi; Lang, Alon; Ben-Horin, Shomron

Department of Gastroenterology, Chaim Sheba Medical Center affiliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Digestion, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22095142

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) patients suffer from significant morbidity and diminished life quality. The plant cannabis is beneficial in various gastrointestinal diseases, stimulating appetite and causing weight gain. Our aims were to assess whether treatment with inhaled cannabis improves quality of life, disease activity and promotes weight gain in these patients. METHODS: Patients with long-standing IBD who were prescribed cannabis treatment were included. Two quality of life questionnaires and disease activity indexes were performed, and patient's body weight was measured before cannabis initiation and after 3 months' treatment. RESULTS: Thirteen patients were included. After 3 months' treatment, patients reported improvement in general health perception (p = 0.001), social functioning (p = 0.0002), ability to work (p = 0.0005), physical pain (p = 0.004) and depression (p = 0.007). A schematic scale of health perception showed an improved score from 4.1 ± 1.43 to 7 ± 1.42 (p = 0.0002). Patients had a weight gain of 4.3 ± 2 kg during treatment (range 2-8; p = 0.0002) and an average rise in BMI of 1.4 ± 0.61 (range 0.8-2.7; p = 0.002). The average Harvey-Bradshaw index was reduced from 11.36 ± 3.17 to 5.72 ± 2.68 (p = 0.001). 

CONCLUSIONS: Three months' treatment with inhaled cannabis improves quality of life measurements, disease activity index, and causes weight gain and rise in BMI in long-standing IBD patients.

Patterns of use of medical cannabis among Israeli cancer patients: a single institution experience

Waissengrin, Barliz; Urban, Damien; Leshem, Yasmin; Garty, Meital; Wolf, Ido

Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel.

Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;

Journal of Pain and Symptom Management, 2015

http://www.ncbi.nlm.nih.gov/pubmed/24937161

The use of the cannabis plant (Cannabis sativa L.) for the palliative treatment of cancer patients has been legalized in multiple jurisdictions including Israel. Yet, not much is currently known regarding the efficacy and patterns of use of cannabis in this setting. OBJECTIVES: To analyze the indications for the administration of cannabis among adult Israeli cancer patients and evaluate its efficacy. METHODS: Efficacy and patterns of use of cannabis were evaluated using physician-completed application forms, medical files, and a detailed questionnaire in adult cancer patients treated at a single institution. RESULTS: Of approximately 17,000 cancer patients seen, 279 (<1.7%) received a permit for cannabis from an authorized institutional oncologist. The median age of cannabis users was 60 years (range 19-93 years), 160 (57%) were female, and 234 (84%) had metastatic disease. Of 151 (54%) patients alive at six months, 70 (46%) renewed their cannabis permit. Renewal was more common among younger patients and those with metastatic disease. Of 113 patients alive and using cannabis at one month, 69 (61%) responded to the detailed questionnaire. Improvement in pain, general well-being, appetite, and nausea were reported by 70%, 70%, 60%, and 50%, respectively. Side effects were mild and consisted mostly of fatigue and dizziness.

CONCLUSION: Cannabis use is perceived as highly effective by some patients with advanced cancer and its administration can be regulated, even by local authorities. Additional studies are required to evaluate the efficacy of cannabis as part of the palliative treatment of cancer patients.

 
 
Invitro and preclinical animal studies

Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts

Kogan, Natalya M.; Melamed, Eitan; Wasserman, Elad; Raphael, Bitya; Breuer, Aviva; Stok, Kathryn S.; Sondergaard, Rachel; Escudero, Ana V. Villarreal; Baraghithy, Saja; Attar-Namdar, Malka; Friedlander-Barenboim, Silvina; Mathavan, Neashan; Isaksson, Hanna; Mechoulam, Raphael; Müller, Ralph; Bajayo, Alon; Gabet, Yankel; Bab, Itai

Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.

Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel.

Institute for Biomechanics, ETH Zürich, Zürich, Switzerland.

Department of Oral Medicine, Hadassah-Hebrew University Faculty of Dental Medicine, Jerusalem, Israel.

Department of Biomedical Engineering, Lund University, Lund, Sweden.

Department of Orthopedics, Lund University, Lund, Sweden.

Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research, 2015

http://www.ncbi.nlm.nih.gov/pubmed/25801536   

Cannabinoid ligands regulate bone mass, but skeletal effects of cannabis (marijuana and hashish) have not been reported. Bone fractures are highly prevalent, involving prolonged immobilization and discomfort. Here we report that the major non-psychoactive cannabis constituent, cannabidiol (CBD), enhances the biomechanical properties of healing rat mid-femoral fractures. The maximal load and work-to-failure, but not the stiffness, of femurs from rats given a mixture of CBD and Δ(9) -tetrahydrocannabinol (THC) for 8 weeks were markedly increased by CBD. This effect is not shared by THC (the psychoactive component of cannabis), but THC potentiates the CBD stimulated work-to-failure at 6 weeks postfracture followed by attenuation of the CBD effect at 8 weeks. Using micro-computed tomography (μCT), the fracture callus size was transiently reduced by either CBD or THC 4 weeks after fracture but reached control level after 6 and 8 weeks. The callus material density was unaffected by CBD and/or THC. By contrast, CBD stimulated mRNA expression of Plod1 in primary osteoblast cultures, encoding an enzyme that catalyzes lysine hydroxylation, which is in turn involved in collagen crosslinking and stabilization. Using Fourier transform infrared (FTIR) spectroscopy we confirmed the increase in collagen crosslink ratio by CBD, which is likely to contribute to the improved biomechanical properties of the fracture callus.

 

Taken together, these data show that CBD leads to improvement in fracture healing and demonstrate the critical mechanical role of collagen crosslinking enzymes.


 

CB1 cannabinoid receptors mediate endochondral skeletal growth attenuation by Δ9-tetrahydrocannabinol

Wasserman, Elad; Tam, Joseph; Mechoulam, Raphael; Zimmer, Andreas; Maor, Gila; Bab, Itai

Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.

Annals of the New York Academy of Sciences, 2015

http://www.ncbi.nlm.nih.gov/pubmed/25573322

The endocannabinoid (EC) system regulates bone mass. Because cannabis use during pregnancy results in stature shorter than normal, we examined the role of the EC system in skeletal elongation. We show that CB1 and CB2 cannabinoid receptors are expressed specifically in hypertrophic chondrocytes of the epiphyseal growth cartilage (EGC), which drives vertebrate growth. These cells also express diacylglycerol lipases, critical biosynthetic enzymes of the main EC, and 2-arachidonoylglycerol (2-AG), which is present at significant levels in the EGC. Femora of CB1- and/or CB2-deficient mice at the end of the rapid growth phase are longer compared to wild-type (WT) animals. We find that Δ(9) -tetrahydrocannabinol (THC) slows skeletal elongation of female WT and CB2-, but not CB1-, deficient mice, which is reflected in femoral and lumbar vertebral body length. This in turn results in lower body weight, but unaltered fat content. THC inhibits EGC chondrocyte hypertrophy in ex vivo cultures and reduces the hypertrophic cell zone thickness of CB1-, but not CB2-, deficient mice.

 

These results demonstrate a local growth-restraining EC system in the EGC. The relevance of the present findings to humans remains to be studied.

 

Cannabinoids decrease the th17 inflammatory autoimmune phenotype

Kozela, Ewa; Juknat, Ana; Kaushansky, Nathali; Rimmerman, Neta; Ben-Nun, Avraham; Vogel, Zvi

The Dr Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Journal of Neuroimmune Pharmacology: The Official Journal of the Society on NeuroImmune Pharmacology, 2013

http://www.ncbi.nlm.nih.gov/pubmed/23892791

Cannabinoids, the Cannabis constituents, are known to possess anti-inflammatory properties but the mechanisms involved are not understood. Here we show that the main psychoactive cannabinoid, Δ-9-tetrahydrocannabinol (THC), and the main nonpsychoactive cannabinoid, cannabidiol (CBD), markedly reduce the Th17 phenotype which is known to be increased in inflammatory autoimmune pathologies such as Multiple Sclerosis. We found that reactivation by MOG35-55 of MOG35-55-specific encephalitogenic T cells (cells that induce Experimental Autoimmune Encephalitis when injected to mice) in the presence of spleen derived antigen presenting cells led to a large increase in IL-17 production and secretion. In addition, we found that the cannabinoids CBD and THC dose-dependently (at 0.1-5 μM) suppressed the production and secretion of this cytokine. Moreover, the mRNA and protein of IL-6, a key factor in Th17 induction, were also decreased. Pretreatment with CBD also resulted in increased levels of the anti-inflammatory cytokine IL-10. Interestingly, CBD and THC did not affect the levels of TNFα and IFNγ. The downregulation of IL-17 secretion by these cannabinoids does not seem to involve the CB1, CB2, PPARγ, 5-HT1A or TRPV1 receptors.

 

In conclusion, the results show a unique cannabinoid modulation of the autoimmune cytokine milieu combining suppression of the pathogenic IL-17 and IL-6 cytokines along with boosting the expression of the anti-inflammatory cytokine IL-10.

 

Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice

Kozela, Ewa; Lev, Nirit; Kaushansky, Nathali; Eilam, Raya; Rimmerman, Neta; Levy, Rivka; Ben-Nun, Avraham; Juknat, Ana; Vogel, Zvi

The Dr. Miriam and Sheldon G. Adelson Center for Biology of Addictive Diseases, Physiology and Pharmacology Department, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

British Journal of Pharmacology, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21449980

BACKGROUND AND PURPOSE: Cannabis extracts and several cannabinoids have been shown to exert broad anti-inflammatory activities in experimental models of inflammatory CNS degenerative diseases. Clinical use of many cannabinoids is limited by their psychotropic effects. However, phytocannabinoids like cannabidiol (CBD), devoid of psychoactive activity, are, potentially, safe and effective alternatives for alleviating neuroinflammation and neurodegeneration. EXPERIMENTAL APPROACH: We used experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice, as a model of multiple sclerosis. Using immunocytochemistry and cell proliferation assays we evaluated the effects of CBD on microglial activation in MOG-immunized animals and on MOG-specific T-cell proliferation. KEY RESULTS: Treatment with CBD during disease onset ameliorated the severity of the clinical signs of EAE. This effect of CBD was accompanied by diminished axonal damage and inflammation as well as microglial activation and T-cell recruitment in the spinal cord of MOG-injected mice. Moreover, CBD inhibited MOG-induced T-cell proliferation in vitro at both low and high concentrations of the myelin antigen. This effect was not mediated via the known cannabinoid CB(1) and CB(2) receptors.

 

CONCLUSIONS AND IMPLICATIONS: CBD, a non-psychoactive cannabinoid, ameliorates clinical signs of EAE in mice, immunized against MOG. Suppression of microglial activity and T-cell proliferation by CBD appeared to contribute to these beneficial effects.

Cannabidiol arrests onset of autoimmune diabetes in NOD mice

Weiss, Lola; Zeira, Michael; Reich, Shoshana; Slavin, Shimon; Raz, Itamar; Mechoulam, Raphael; Gallily, Ruth

Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Neuropharmacology, 2008

http://www.ncbi.nlm.nih.gov/pubmed/17714746

We have previously reported that cannabidiol (CBD) lowers the incidence of diabetes in young non-obese diabetes-prone (NOD) female mice. In the present study we show that administration of CBD to 11-14 week old female NOD mice, which are either in a latent diabetes stage or with initial symptoms of diabetes, ameliorates the manifestations of the disease. Diabetes was diagnosed in only 32% of the mice in the CBD-treated group, compared to 86% and 100% in the emulsifier-treated and untreated groups, respectively. In addition, the level of the proinflammatory cytokine IL-12 produced by splenocytes was significantly reduced, whereas the level of the anti-inflammatory IL-10 was significantly elevated following CBD-treatment. Histological examination of the pancreata of CBD-treated mice revealed more intact islets than in the controls.

 

Our data strengthen our previous assumption that CBD, known to be safe in man, can possibly be used as a therapeutic agent for treatment of type 1 diabetes.

 

HU-331: a cannabinoid quinone, with uncommon cytotoxic properties and low toxicity

Peters, Maximilian; Kogan, Natalya M.

The Hebrew University, Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Jerusalem, Israel

Expert Opinion on Investigational Drugs, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17714026

The oxidation of cannabis constituents has given rise to their corresponding quinones, which have been identified as cytotoxic agents. Out of these molecules the quinone of cannabidiol--the most abundant non-psychoactive cannabinoid in Cannabis sativa--has shown the highest cytotoxicity. This compound was named HU-331 and it exerts antiangiogenic properties, induces apoptosis to endothelial cells and inhibits topoisomerase II in nanomolar concentrations. Unlike other quinones, it is not cardiotoxic and does not induce the formation of free radicals.

 

A comparative in vivo study in mice has shown HU-331 to be less toxic and more effective than the commonly used doxorubicin. This review summarises the properties of HU-331 and compares it with doxorubicin and other topoisomerase II inhibitors.

Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury

Durst, Ronen; Danenberg, Haim; Gallily, Ruth; Mechoulam, Raphael; Meir, Keren; Grad, Etty; Beeri, Ronen; Pugatsch, Thea; Tarsish, Elizabet; Lotan, Chaim

Cardiology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

American Journal of Physiology. Heart and Circulatory Physiology, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17890433

Cannabidiol (CBD) is a major, nonpsychoactive Cannabis constituent with anti-inflammatory activity mediated by enhancing adenosine signaling. Inasmuch as adenosine receptors are promising pharmaceutical targets for ischemic heart diseases, we tested the effect of CBD on ischemic rat hearts. For the in vivo studies, the left anterior descending coronary artery was transiently ligated for 30 min, and the rats were treated for 7 days with CBD (5 mg/kg ip) or vehicle. Cardiac function was studied by echocardiography. Infarcts were examined morphometrically and histologically. For ex vivo evaluation, CBD was administered 24 and 1 h before the animals were killed, and hearts were harvested for physiological measurements. In vivo studies showed preservation of shortening fraction in CBD-treated animals: from 48 +/- 8 to 39 +/- 8% and from 44 +/- 5 to 32 +/- 9% in CBD-treated and control rats, respectively (n = 14, P < 0.05). Infarct size was reduced by 66% in CBD-treated animals, despite nearly identical areas at risk (9.6 +/- 3.9 and 28.2 +/- 7.0% in CBD and controls, respectively, P < 0.001) and granulation tissue proportion as assessed qualitatively. Infarcts in CBD-treated animals were associated with reduced myocardial inflammation and reduced IL-6 levels (254 +/- 22 and 2,812 +/- 500 pg/ml in CBD and control rats, respectively, P < 0.01). In isolated hearts, no significant difference in infarct size, left ventricular developed pressures during ischemia and reperfusion, or coronary flow could be detected between CBD-treated and control hearts.

 

Our study shows that CBD induces a substantial in vivo cardioprotective effect from ischemia that is not observed ex vivo. Inasmuch as CBD has previously been administered to humans without causing side effects, it may represent a promising novel treatment for myocardial ischemia.


 

Cannabidiol lowers incidence of diabetes in non-obese diabetic mice

Weiss, L.; Zeira, M.; Reich, S.; Har-Noy, M.; Mechoulam, R.; Slavin, S.; Gallily, R.

Hadassah University Hospital, Department of Bone Marrow Transplantation & Cancer Immunotherapy, Jerusalem,Israel.

Autoimmunity, 2006

http://www.ncbi.nlm.nih.gov/pubmed/16698671

Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis.

 

Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.

Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model

Lodzki, M.; Godin, B.; Rakou, L.; Mechoulam, R.; Gallily, R.; Touitou, E.

Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel

Journal of Controlled Release: Official Journal of the Controlled Release Society, 2003

http://www.ncbi.nlm.nih.gov/pubmed/14644587

Cannabidiol (CBD) is a new drug candidate for treatment of rheumatic diseases. However, its oral administration is associated with a number of drawbacks. The objective of this study was to design a transdermal delivery system for CBD by using ethosomal carriers. CBD ethosomes were characterized by transmission electron microscopy, confocal laser scanning microscopy and differential scanning calorimetry. Results indicated that CBD and phosphatidylcholine form an eutectic mixture. In vivo application of ethosomal CBD to CDI nude mice produced a significant accumulation of the drug in the skin and in the underlying muscle. Upon transdermal application of the ethosomal system to the abdomen of ICR mice for 72 h, steady-state levels were reached at about 24 h and lasted at least until the end of the experiment, at 72 h. Furthermore, transdermal application of ethosomal CBD prevented the inflammation and edema induced by sub-plantar injection of carrageenan in the same animal model.

 

In conclusion, ethosomes enable CBD's skin permeation and its accumulation in a depot at levels that demonstrate the potential of transdermal CBD to be used as an anti-inflammatory treatment.

 

 

 

 

 

 

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