Importance Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. Objective To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. Data Sources Twenty-eight databases from inception to April 2015. Study Selection Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. Data Extraction and Synthesis Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. Main Outcomes and Measures Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. Results A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.36 [95% CI, −0.69 to −0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. Conclusions and Relevance There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

Thesis (Ph. D.)--University of Sydney, 2001. / Title from title screen (viewed Apr. 22, 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Dept. of Psychology, Faculty of Science. Degree awarded 2001; thesis submitted 2000. Includes bibliography. Also available in print form.

Thesis (Ph.D.)--Aberdeen University, 2009. / Title from web page (viewed on Mar. 26, 2010). Includes bibliographical references.

Thesis (Ph. D.)--Columbia University, 1941. / Vita. "Appendix: ... Marihuana activity of cannabinol types": p. [41]. Bibliography: p. [39].

Thesis (M.Sc.)--York University, 2007. Graduate Programme in Biology. / Typescript. Includes bibliographical references (leaves 64-74). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR38771

Anticonvulsant activity of cannabidiol (CBD) has been well documented in various laboratory animal species and also in man. As part of our continuing effort to study and to define the structure anticonvulsant relationship several analogs of CBD were synthesized wherein its structural units, namely, the terpene ring, aryl ring and/or side chain were systematically modified. These analogs include the: (1) unnatural (+)-Cannabidol (1b), (2) Delta-3-carenyl analog-(+)-carenadiol (45a), its diacetate (45b) and its 1",1"-dimethylheptyl side chain analog (45c), and (3) unnatural 7-acetoxycannabidiol (46b). (+)-Cannabidiol (1b) was synthesized in about 20-25% yield from olivetol (51) and two different p-menthadienols (67 and 70) as monoterpenoid synthons. (-)-p-Mentha-1,8-dien-3-ol (67) was prepared from (-)-limonene (65) by chromium trioxide-pyridine complex oxidation followed by cerium trichloride assisted sodium borohydride reduction of the obtained ketone (66a). (-)-p-Mentha-2,8-dien-1-ol (70) was synthesized from 1:1 mixture of cis- (69a) and trans-epoxide (68a) of limonene (65) in about 35% yield. The reaction involves phenylselenide anion mediated stereospecific trans-diaxial opening of the epoxide ring to give the required alcohol (70) along with its regioisomer (71) as the major product (79%). The delta-3-carenyl analog (+)-carenadiol (45a) was synthesized from car-4-en-3β-ol (80) and olivetol (51) in about 20% yield. Car-4-en-3β-ol (80) was prepared in about 90-95% yield from the corresponding 3β,4β-epoxy carane (77) by following the same methodology described for (70). The compounds were evaluated for anticonvulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rotorod (ROT) test. A general lack of stereoselectivity for the anti-AGS and ROT neurotoxic effects was observed for CBD and its derivatives. Thus (-)-CBD (1a) was marginally more potent than (+)-CBD (1b). But the CBD analog derived from (+)-car-3-ene (72), i.e., (+)-carenadiol (45a), is of interest because of its high protective index (PI = 5.1) and is therefore comparable to(1b) (to which it is stereochemically related) in potency. The 1",1"-dimethylheptyl derivative ((+)-45b), could not separate anticonvulsant activity from neurotoxicity. (Abstract shortened with permission of author.)

Given the recent finding that the cannabinoid receptors CB₁ and CB₂ affect bone metabolism, we examined the role of GPR55 in bone biology. GPR55 was expressed in human and mouse osteoclasts and osteoblasts; expression was higher in human osteoclasts than in macrophage progenitors. Although the GPR55 agonists O-1602 and LPI inhibited mouse osteoclast formation <i>in vitro</i>, these ligands stimulated mouse and human osteoclast polarisation and resorption <i>in vitro</i> and caused activation of Rho and ERK1/2. These stimulatory effects on osteoclast function were attenuated in osteoclasts generated from GPR55^-/- macrophages and by the GPR55 antagonist cannabidiol (CBD). Furthermore, treatment of mice with this non-psychoactive constituent of cannabis significantly reduced bone resorption <i>in vivo</i>. Consistent with the ability of GPR55 to suppress osteoclast formation but stimulate osteoclast function, histomorphometric and microcomputed tomographic analysis of the long bones from male GPR55^-/- mice revealed increased numbers of morphologically-inactive osteoblasts, but a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage. These data reveal a hitherto unrecognised role of GPR55 in bone physiology by regulating osteoclast number and function. In addition, this study also brings to light a newly identified effect of both the endogenous ligand, LPI , on osteoclasts and of the cannabis constituent, CBD, on osteoclasts and bone turnover <i>in vivo</i>. These results suggest that blocking GPR55 with small molecules similar to CBD may be beneficial in bone diseases associated with increased osteoclast activity such as osteoporosis.

The endocannabinoid system functions through two well characterized receptor systems termed CB₁ and CB₂.  However a growing body of evidence exists that suggest that the system is more complicated and indicate the presence of additional receptors.  Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological activities. In this thesis it is demonstrated that GPR55 binds to and is activated by the cannabinoid ligand CP55940. In addition endocannabinoids including anandamide and virodhamine activate GPR55 with nM potencies.  Ligands having no CB₁ or CB₂ activity that are believed to function at some of these novel receptor types such as cannabidiol and abnormal cannabidiol effect activity of GPR55.  These data suggest that GRP55 is a novel cannabinoid receptor, and its relative preference for ligands with respect to CB₁and CB₂ described here will permit delineation of its physiological function.  Data also suggesting that GRP55 couples to Gα13 and can mediate activation of RhoA, rac1 and cdc42.  It’s also demonstrated that GPR55 is functionally expressed in the mouse brain and using CB₁ and GPR55 selective ligands it is possible to functionally distinguish these receptors. It is therefore probable that both these receptors contribute to cannabinoid activity in CNS function.

Changes in the expression of the cannabinoid receptor 1 (CB1) has been associated with the progression of many human diseases such as anxiety and depression, schizophrenia, epilepsy, Huntington’s disease, Parkinson’s disease, obesity and osteoporosis. However, little is known about the mechanisms that control CB1 expression or how they may be affected by human polymorphic variation to bring about disease susceptibility. In order to elucidate the regulatory systems controlling the tissue specific transcriptional regulation of the CNR1 gene, that encodes CB1, and the effects of human polymorphisms on these systems, this study combined comparative genomics, molecular biology, cell biology and pharmacology with human genetics. Comparative genomics was used to identify five evolutionary conserved regions (ECR) 5’ of the CNR1 gene that had been conserved between humans and birds (310 million years). Primary cell culture, using luciferase reporter constructs and transgenic studies suggested that some of these regions acted as enhancers which controlled gene expression in a tissue specific manner. In addition, it was demonstrated that the activity of these ECRs can be altered using different signal transduction agonists. More importantly, evidence is provided to suggest that ECR1 and the endogenous CNR1 promoter work synergistically in primary dorsal root ganglia (DRG) neurons and that ECR2 and the CNR1 promoter work synergistically in primary hypothalamic neurons in response to MAPK and ER agonists. Furthermore, a validated human SNP within ECR1 can interfere with a putative AP-1 transcription factor binding site when the major allele is present to block the up-regulation seen with a MAPK agonist in hippocampal neurons. The discovery of such novel cell specific regulatory pathways and the recognition of the cell specific effects of polymorphisms on these pathways may lead to a better understanding of how CNR1 mis-expression can contribute to disease and will enhance our ability to develop novel therapies.

Cancer is a growing health concern world-wide and is the second most common cause of death after heart diseases. Current treatment strategies such as surgery, chemotherapy and radiation provide some relief to cancer patients but the toxic side effects associated with chemotherapy and radiation often lead to further adverse health effects. Hence there is a need for drugs with better safety profile and improved efficacy. Cannabinoids are a group of compounds with several therapeutic properties and besides their appetite stimulant, anti-emetic and analgesic effects, cannabinoids can inhibit tumor growth, survival and metastasis. The mechanisms of action of cannabinoids as anticancer agents are highly complex and not completely understood. Studies from our laboratory indicate that the specificity protein (Sp) transcription factors, Sp1, Sp3 and Sp4 that belong to the Sp/KLF family of transcription factors are overexpressed in many tumors and regulate critical factors responsible for cancer cell proliferation, growth, angiogenesis and survival. Hence, we hypothesized that cannabinoids elicit their responses on cancer cells by downregulating the expression of Sp proteins and Sp-regulated gene products. Treatment of colon and prostate cancer cells with the cannabinoids WIN and cannabidiol (CBD) inhibited cancer cell proliferation, induced apoptosis and downregulated Sp proteins and Sp-dependent genes. Furthermore, we demonstrated that WIN and CBD-mediated induction of apoptosis and repression of Sp proteins were mediated by phosphatases and that the phosphatase involved in WIN- dependent downregulation of Sp proteins was protein phosphatase 2A (PP2a). In addition WIN induced expression of ZBTB-10, an Sp repressor and downregulated microRNA-27a (miR27a) and these effects were PP2a-dependent indicating that WIN transcriptionally represses Sp protein expression by activating the phosphatase, PP2a. We also investigated the effects of 1,1-bis(3'-indolyl)-1-(p-bromophenyl)methane (DIM-C-pPhBr) and the 2,2'-dimethyl analog (2,2'-diMeDIM-C-pPhBr), on survivin expression in colon and pancreatic cancer cells. Survivin is an anti-apoptotic protein associated with cancer cell survival and confers radiation-resistance in patients receiving radiotherapy. In addition radiation induces survivin, leading to radioresistance in tumors. In this study we demonstrated that DIM-C-pPhBr and 2,2'-diMeDIM-C-pPhBr inhibit cell proliferation and induce apoptosis in colon and pancreatic cancer cells and in combination with radiotherapy, these drugs suppress radioresistance by inhibiting radiation induced survivin.