Roderick Hoover War on Drugs Professor Rob Kirby Cannabinoids and Their Potential: an Overview of the Endocannabinoid System

and its Viability as a Possible Anticancer Agent

Cannabis has been ingested, smoked, or, more recently, vaporized in order to receive its recreational and medicinal effects. With the technological advancements made within the last 100 years, scientists and researchers have been able to pinpoint many medicinal uses of cannabis such as easing the effects of glaucoma, multiple sclerosis, anorexia, nausea, and pain associated with various diseases, as well as with cancer itself. However, the objective of this paper is to examine the recent findings in cancer treatment by use of both synthetic and naturally occurring cannabinoids, as well as to give one a feeling for the sort of testing that has been going on in the past decade and a half in the ever-growing field of endocannabinoid research. Both Cannabis sativa and Cannabis indica are unique to the plant world in that they produce a variety of around 60 cannabinoids, the active ingredients in marijuana. Out of these 60 cannabinoids, THC has been pinpointed as the most psychoactive, leading to many of the hallucinogenic properties associated with marijuana. The reason that THC is able to have such effects on the mind and body is due to the fact that cannabinoid receptors known as CB1 and CB2 exist naturally in many parts of the brain and body. Within the brain itself, cannabinoid receptors have been localized using autoradiography, which shows a general tendency for cannabinoid receptors to be located in the hippocampus, cerebellum, and forebrain regions. The fact that cannabinoid receptors are generally sparse in the areas that control cardiovascular and breathing functions helps to explain why high levels of cannabis do not lead to death (Miles Herkenham,

1990). The most consistent finding regarding cannabis usage, both in humans, dogs, rats, and monkeys links cannabis usage to a decrease in short-term memory tasks and abilities, which is linked to the large proportion of cannabinoid receptors in the hippocampus. Many of these shortterm memory deficits mimic the effects of herpes simplex encephalitis, Korsakoff syndrome, or Alzheimer's disease (Sullivan, 2000). While the short-term effects of cannabis have been sought by many users, researchers and scientists have made unprecedented advancements in the understanding of the endocannabinoid system, which may have a promising future in the possible management and treatment of various cancers in humans. A brief overview of what the endocannabinoid system is follows below. The endocannabinoid (endogenous cannabinoids) system was discovered in 1992 and refers to the CB1 and CB2 receptors and their effects on cells. These receptors are present in many mammalians, and their effects differ based on where in the body they are located. CB1 is the receptor located in and around the central nervous system, especially the brain, and acts as a neuromodulator, which inhibits the release of various neurotransmitters. It is also responsible for the high people get from smoking marijuana. CB2, located in various other body tissues, has been shown to change how proteins and nuclear factors are responsible for cell proliferation, differentiation, and apoptosis (Maurizio Bifulco, 2006). The two most known endocannabinoids produced by mammals are AEA (Anandamide) and its derivative, 2-AG. Since the discovery of the endocannabinoid system, scientists have been able to create several analogues to THC that bind to the same receptors, CB1 and CB2. The affinity with which each of these synthetic versions of THC binds to CB1 and CB2 varies and changes its effect.

Table 1 (Maurizio Bifulco, 2006) summarizes many of the common cannabinoids currently being researched as well as their affinity for the CB1 or CB2 receptor and potential therapeutic uses. Note the presence of delta-9-tetrahydrocannabinol, the primary active component of cannabis. THC is considered a plant-derived cannabinoid, AEA and 2-AG are endogenous (produced by the body), and the rest are synthetic versions currently used to study the endocannabinoid system. Two antagonists, SR141716 for CB1 and SR144528 for CB2, have also been developed and studied for the advancement of endocannabinoid knowledge (Guzmn, 2003). The number of cannabinoids used in research continues to grow. Many studies have been done on the effects of cannabinoids on different tumors, both in vitro (under lab conditions) and in vivo (within a living host). Depending on the circumstances and sort of cannabinoid used, varied effects have been observed. Research into the viability of using cannabinoids to fight breast cancer, prostate cancer, gliomas, colorectal cancer, lung, brain, and skin cancers has led to some very interesting findings (Marijuana May Fight Lung Tumors, 2007). Past and current studies are finding more and more evidence to support cannabinoids as a

possible treatment option for many forms of cancer exhibiting CB1, CB2, and vanilloid receptors.

Table 2 (Guzmn, 2003) conveniently lists many of the current findings into cannabinoid effects on various forms of cancer, as well as which receptor has been linked to these effects. Note that this table only covers relevant data up to the year 2003. Since then, other findings have become available further classifying exactly which receptors may help stem the growth of cancers, many of which will be discussed later in this paper. Also note that many of the studies listed as in vitro have moved on to in vivo testing in mice, such as the effects of cannabinoids on prostate carcinoma, which again will be discussed later in this paper. For references listed on the table, as well as a comprehensive viewpoint on the status of endocannabinoid research as of 2003, visit the Guzmn article listed in the works cited. A very new, updated version of this research is included attached at the end of this paper. (Gertsch, 2010) Breast Cancer The first study to examine is one done on mice in order to determine the possible effectiveness of using THC derivatives in fighting off a few common strains of human breast cancer, when injected into mice. In this study, the effects of a synthetic derivative of THC

known as SR141716 acts as an antagonist (deactivator) to the CB1 receptors found on various common strains of human breast cancer. In this study, it was found that SR141716 decreased the rate at which the breast cancer tumors grew in mice by exhibiting an anti-proliferative effect, separate from any signs of apoptosis that will be discussed in later studies. (Daniela Sarnataro, 2006)

Table 3 (Daniela Sarnataro, 2006). These graphs measure the effect that the SR141716 cannabinoid has on cancer volume after 20 days in mice. The first three graphs (MDA-MB-231, MCF-7, and T47D) express CB1 receptors in varying degrees, while the last graph (CHO) represents a strain with zero CB1 receptors. The researchers stated that this data show that this particular cannabinoid reduces cancer proliferation through the CB1 pathway in a dosedependent manner. It was further noted that SR141716 had the greatest effect on the more invasive forms of cancer, while having no degrading effect on normal cells (Daniela Sarnataro, 2006).

The study described above is only one of many studies done on cannabinoid effect on breast cancer cells. The results of one in vitro study done in 1998 show a remarkable ability of cannabinoids, specifically anandamide (AEA) to decrease the cell proliferation of mammary cancer cells. In this particular study, AEA was shown to decrease the proliferation of both EFM19 and MCF-7 strains of human breast cancer. The relevant results are shown below in Table 4.

Table 4 (Luciano De Petrocellis, 1998). Table A represents the proliferative effects of differing doses of AEA on EFM-19 and MCF-7 strains, where 100% cell would represent no effect on cell proliferation, while 0% would represent a complete stopping of cell proliferation. Table B helps quantify these findings by presenting a comparison of the growth curves of a control versus two different concentrations of AEA over a period of 144 hours. Here, it is clearer that the effects of AEA on cancer growth are indeed dose-dependent, with the AEA 10 micromolar concentration having a very pronounced effect in decreasing the rate of cancer cell proliferation. Researchers were able to conclude by the end of the study that the endogenous cannabinoid anandamide dose dependently inhibited the proliferation of MCF-7 and EFM-19 cells, with a maximum of 83-92% inhibition at 5-10 micromoles. They went on to suggest that anandamide works through CB1

receptor-mediated inhibition of endogenous prolactin action by interfering with the prolactin receptors on EFM-19 and MCF-7 cells (Luciano De Petrocellis, 1998).

The results of these studies, that cannabinoids can be selectively used to treat various forms of human breast cancer through CB1-regulated pathways, are being tested again and again, with promising results pointing toward a possible treatment option for humans in the future. But breast cancer is not the only form of cancer that cannabinoids have been tested upon. Prostate Cancer As the most common form of cancer in men, prostate cancer has become a major lifethreatening disease in many Western countries. The US has an increasing problem with prostate cancer, and current methods are inadequate in treating it. Here, multiple studies have shown that cannabinoids may be able to help in fighting the growth rate of prostate cancer, as well as inducing apoptosis in some cancer cells. Differentiating from the CB1-reliant effects seen in breast cancer treatments, cannabinoids may be used to affect both the CB1 and CB2 receptors in different ways (Sami Sarfaraz, 2007). After asserting that the expression of CB1 and CB2 receptors was much higher in cancerous prostate cells than normal cells, scientists at the University of Wisconsin investigated the effects of cannabinoid WIN-55,212-2 (a mixed CB1/CB2 agonist) on PrEC normal prostate epithelial cells and LNCaP androgen-sensitive prostate cancer cells. In this in vitro experiment, the results were once more promising, showing a dose-dependent and time-dependent inhibition of cell growth and viability, with little effect on normal cells (Sami Sarfaraz F. A., 2005).

Table 5 (Sami Sarfaraz F. A., 2005). <See related article for complete table> Table 5A on the previous page shows the dose-dependent relationship between the molarity of WIN-55,212-2 administered to the cells and their subsequent viability at the end of 24 and 48 hours. The normal prostate cells (PrEC) experienced little degradation of cell viability with increased dosages, while cancerous LNCaP cells experienced a marked drop in cell viability, indicating that WIN-55,212-2 is effective at inhibiting the growth of cells. Table 5C shows the comparative effect of WIN-55,212-2 after 24 hours on LNCaP cells, using the annexin V-FLUOS staining kit. The kit shows both apoptotic (green) and necrotic (red) cells. It can easily be seen that the number of cells undergoing apoptosis or already dead increases dramatically with each increase in dosage (Sami Sarfaraz F. A., 2005). This experiment was later repeated with SR141716 (a CB1 antagonist) and SR144528 (a CB2 antagonist). It was shown that when LNCaP cells were treated with each of these antagonists, the WIN-55,212-2 had little effect on cell viability, meaning that the receptors responsible for inhibiting the growth of LNCaP cells were indeed CB1 and CB2. The writers of this experiment, who have since performed more experiments pinpointing the exact mechanisms involved in this growth inhibition, concluded that cannabinoids have a promising future in terms of possible cancer treatments, and should be studied further (Sami Sarfaraz F. A., 2005).

The next study performed both an in vitro and in vivo portion in an attempt to recognize the role of CB2 expression in tumor cells. The in vivo portion will be focused on, but the results of the study as a whole will also be summarized. The in vivo portion was performed on living mouse specimens, and sought to determine the possible effectiveness of cannabinoid JWH-015 in the treatment of the common strain of prostate cancer, PC-3. Again, the results were promising, and experimenters were further able to narrow down how the cannabinoids induce apoptosis and growth inhibition in androgen-resistant PC-3 cells. The experiment was done on mice that had been injected with PC-3 cells four weeks before and now had an average tumor volume of 70mm3. Each day thereafter, the mice were injected with a saline solution, a JWH015 solution, or a mixture of JWH-015 and SR 144528 (SR2) to determine whether the effects of JWH-015 were indeed due to CB2 receptor activation. SR2 antagonizes CB2, thereby nullifying its expression (N Olea-Herrero, 2009).

Table 6 (N Olea-Herrero, 2009). Tables 6A and 6B illustrate the respective effectiveness of JWH-015 and JWH-015 plus SR2 in reducing tumor volume. The tumor volume (versus day 0, average tumor volume=70mm3) is much smaller in those mice treated with only JWH-015, as opposed to the unopposed control group and the JWH-015 plus SR2 CB2 antagonist.

Table 7 (N Olea-Herrero, 2009). This table quantifies the results in Table 6, comparing the initial and final tumor volumes, growth percentages, and final tumor weights. These findings not only give great support for the anticancer nature of cannabinoids, but also confirm that, in PC-3 cells, the anticancer effect comes about through activation of CB2 receptors. In the earlier in vitro portion of the experiment, CB2 was shown to induce a de novo synthesis of ceramide in tumor cells. Ceramide generally mediates anti-proliferative actions of cells, such as the inhibition of growth, induction of apoptosis, and mediation of senescence. Through a series of stress-related pathways, CB2 activation was shown to have a regulatory effect p38 MPAK and JNK activation, as well as increasing ceramide and other stress-related genes. The accumulation of ceramide in cancer cells has been shown to promote cell death in cancer cells. As a whole, the study helps scientists to understand the cell-signaling pathways of cannabinoids, especially CB2, in the treatment of cancer in vitro and in vivo (N Olea-Herrero, 2009). Thyroid Cancer Thyroid cancer is another area in which cannabinoids have shown substantial effect in reducing tumor volume. One study used the cannabinoid Met-F-AEA in order to determine its effectiveness on both primary rat thyroid cancer (TK-6) cells and metastasis-derived thyroid cancer (MPTK-6). This study examined consisted of multiple parts including both in vivo and in vitro testing, and some of these results will be described on the following page.

Table 8 (Giuseppe Portella, 2003). Table 8A shows the effects of cannabinoid MET-F-AEA on primary thyroid cancer cells (TK-6) and metastasis-derived thyroid cancer cells (MPTK-6). This in vitro experiment had a culture of both types of cells incubated with a 10 micro molar solution of MET-F-AEA. The AEA once more significantly inhibited the growth of these cancer cells. Table 8B shows the effect that MET-F-AEA has on already established tumors. In an in vivo portion of the experiment, K-ras-transformed thyroid FRTL-5 (Ki Mol) cells were injected into mouse paws, and after tumors were clearly detectable, a solution of either 0.5 mg/kg/dose METF-AEA or 0.7 mg/kg/dose MET-F-AEA+SR141716A (CB1 antagonist) were administered and tumor volume checked weekly. This experiment shows the CB1-dependent nature of the cannabinoids effectiveness on this particular form of cancer, as decreased expression of the CB1 receptor via the SR141716A antagonist resulted in similar tumor volumes in mice. These results support that CB1 agonists may be used as a therapeutic approach to slow tumor growth in vivo by inhibiting at once tumor growth, angiogenesis, and metastasis (Giuseppe Portella, 2003). Thyroid carcinomas are yet another example of how endocannabinoid research and THC derivatives have been used to slow tumor growth via the CB1 receptor. Other studies (not mentioned) confirm the data shown.

Leukemia According to the Leukemia and Lymphoma Society, leukemia in its various forms will claim the lives of approximately 21,840 people living in the United States in the year 2010. Once more, cannabinoids working through CB receptor-related pathways have been suggested and tested as a possible treatment. A study performed in 2006 sought to explore possible CB2 pathway treatments, without the psychoactive effects found in many CB1/CB2 nonselective agonists. CBD (cannabidiol) is a non-psychoactive cannabinoid found naturally in the Cannabis sativa plant. The designers of this study had already done preliminary testing of cannabinoids on various forms of cancer, and chose this time to try to determine the effects and mechanisms behind the use of CBD on murine EL-4 leukemia and the human Jurkat and Molt-4 leukemia cell lines. Both in vitro (on mice) and in vivo testing methods were used once more, and some of the relevant results are as follows.

Table 9 (Robert J. McKallip, 2006). Table 9A shows the effects in vivo of varying concentrations of CBD on the EL-4 leukemia cell line. As with previous studies, the number of cancer cells dropped significantly in a dose-dependent manner. Table 9B shows the role of CB1, CB2, and VR1 in mediating the effects of CBD on EL-4 cell viability was determined by culturing EL-4 tumor cells with 5 micro mole CBD in the presence or absence of CB1

(SR141716A, 5 micro mole), CB2 (SR144528, 5 micro mole), or VR1 (CPZ, 5micro mole) antagonists. These results show the majority of the apoptotic potential from CBD comes from its effect on the CB2-regulated pathways in tumor cells, due to the fact that when CB2 expression was inhibited, the cancer-reducing effect was also inhibited. Very similar results were reached with in vitro testing of CBDs effects on the Jurkat and MOLT-4 cell lines (see reference for tables) (Robert J. McKallip, 2006).

Table 10 (Robert J. McKallip, 2006). Table 10 (above) shows the results of in vivo testing on live mice, which were injected with varying degrees of CBD 10 days after being injected with 1x106 EL-4 leukemia cancer cells. The number of viable cells was measured one day later, as well as the percentage of recovered tumor cells that tested positive for apoptosis via the TUNEL method (Robert J. McKallip, 2006). Not only did the designers of this experiment test the effectiveness of cannabidiol in fighting off some common forms of leukemia, but they also determined that the cannabinoid receptor CB2 was responsible for the majority of this action. Furthermore, they determined that the likely mechanism of action involved in this induction of apoptosis was increased levels of ROS (Reactive oxygen species) production as well as an increase in the expression of NAD(P)H oxidases Nox4 and p22phox(both of which have a role in the generation of ROS). It was noted

that when ROS scavengers were placed in the samples, the inhibitory actions of CBD decreased drastically. The researchers also noted that CBDs role on leukemia had little to do with ceramide levels, as inhibiting ceramide production via an antagonist had little effect, contrasting other studies done on ceramide-producing agents, such as THC and JWH-015 (discussed earlier). The researchers went on to state that the ceramide-induced apoptosis and ROS-apoptotic actions on cells are likely due to independent pathways, and that a combination of CBD and THC could prove very effective in fighting cancers such as leukemia. They concluded that more research should be done on the exact cellular pathways involved in reaching these effects, but that this research could lead to the inception of a new, highly-selective anticancer agent (Robert J. McKallip, 2006). Gliomas Gliomas are one of the most malignant and difficult to treat forms of cancer. Glial cells play a major role in brain function since they are involved in processes such as the homeostasis of the neuronal microenvironment, the formation of the blood-brain barrier, the guidance of neuron migration in the developing embryo, and the secretion of neurotrophic factors for neuron healing or development (Cristina Snchez I. G.-R., 1998). A study done in 1998 that found that THC induced C6.9 glioma cell apoptosis was later followed up by a 2001 study that confirmed initial data suggesting that the majority of antitumor activity of cannabinoids on glioma cells was due to the presence of CB2 receptors, as opposed to CB1 receptors, which THC primarily acts upon. The 2001 study used the synthetic CB2 agonist JWH133 in order to judge whether or not it was possible to use a non-psychoactive cannabinoid to treat cancer. Mice previously injected with C6-cell gliomas were injected with either a control, a JWH-133 compound, a JWH-133 plus CB2 antagonist compound, a JWH-133 plus CB1

compound, a WIN-55,212-2 (nonselective to CB1 or CB2) or WIN-55,212-2 plus CB1 or CB2 antagonist. The results (not shown) indicated that indeed, C6-cell glioma growth was significantly inhibited by the JWH-133 in a manner similar to the WIN-55 agent, without any of the psychoactive effects found in the nonselective WIN-55 cannabinoid. As seen in other forms of cancer, the pro-apoptotic effect of JWH-133 was attributed with the synthesis of ceramide and its subsequent buildup in cancerous cells (Cristina Snchez M. L.-R., 2001). The results of these studies, along with others not mentioned, support the assertion that glial malignancies may be able to be treated with the therapeutic use of cannabinoids. Other Forms of Cancer In addition to having positive effects on breast cancer, thyroid cancer, prostate cancer, leukemia, and gliomas, there are other forms of cancer on which cannabinoids are thought to influence. In colon cancer cells, ceramide production has been linked to either the CB1 or CB2 receptor activation, with similar anti-proliferative and pro-apoptotic effects seen in prostate cancers and gliomas. Lung cancers, lymphomas, pancreatic cancer, cervix cancer, melanoma, skin tumors, cholangiocarcinomas, and hepatomas have all been tested on with favorable anticancer results (Gertsch, 2010). In order to see exact cell lines, effects on cancers, compounds tested, and in vivo status, see the attached table at the end of the paper (courtesy of Gertsch, 2010). Conclusion By now, it should be fairly obvious that cannabinoids have a very real future in the treatment of cancers. Cannabinoids working on the CB1, CB2, and related pathways have had much promise in the field of cancer reduction, as well as having a possible use as cancerpreventing agents. However, the extreme complexity and many, many possible routes of action

have left scientists at a near standstill. The major and unanimous effect of cannabinoids on CBexpressing tumors is its anti-proliferative effect, however cannabinoids have also been shown to reduce angiogenesis, cell migration and metastasis, inhibit carcinogenesis and reduce inflammation (Gertsch, 2010). These effects, while all positive in their own way, are highly variable and still poorly understood. It has been shown that the response of cancers to different cannabinoids depends on the cell type, the activation of certain signal transduction pathways, the form of the drug, the timing of the drug relative to cancer onset, and the expression of the cannabinoid receptor genes on both normal and tumor cells (Maurizio Bifulco, 2006). As scientists attempt to sort through the mountains of data and conflicting evidence, the only thing that has remained clear from day one is: there is still much work to be done before we have any chance of reliably using cannabinoids as a treatment for cancer in humans.

Works Cited
Marijuana May Fight Lung Tumors. (2007, April 17). Retrieved October 10, 2010, from CBS News: http://www.cbsnews.com/stories/2007/04/17/health/webmd/main2696726.shtml#comments Leukemia Facts and Statistics. (2010, October 11). Retrieved October 12, 2010, from The Leukemia and Lymphoma Society: http://www.leukemia-lymphoma.org/all_page?item_id=9346 Cristina Snchez, I. G.-R. (1998, September 25). 9-Tetrahydrocannabinol induces apoptosis in C6 glioma cells. Retrieved October 11, 2010, from FEBS Letters: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T36-3TX4VC22&_user=440026&_coverDate=09/25/1998&_rdoc=1&_fmt=high&_orig=search&_origin=search &_sort=d&_docanchor=&view=c&_acct=C000020939&_version=1&_urlVersion=0&_userid=440 026&md5=18b5fc5db1126 Cristina Snchez, M. L.-R. (2001, August 1). Inhibition of Glioma Growth in Vivo by Selective Activation of the CB2 Cannabinoid Receptor. Retrieved October 12, 2010, from Cancer Research: http://cancerres.aacrjournals.org/content/61/15/5784.full Daniela Sarnataro, S. P. (2006, October). The Cannabinoid CB1 Receptor Antagonist Rimonabant (SR141716) Inhibits Human Breast Cancer Cell Proliferation through a Lipid Raft-Mediated Mechanism. Retrieved October 9, 2010, from Molecular Pharmacology: http://molpharm.aspetjournals.org/content/70/4/1298.full Gertsch, S. O. (2010, January 8). Cannabinoid receptor ligands as potential anticancer- high hopes for new therapies? Retrieved October 11, 2010, from Pharmacy and Pharmacology: http://onlinelibrary.wiley.com/doi/10.1211/jpp.61.07.0002/pdf Giuseppe Portella, C. L. (2003, July 3). Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. Retrieved October 12, 2010, from FASEB Journal: http://www.fasebj.org/cgi/reprint/02-1129fjev1 Guzmn, M. (2003, October). Cannabinoids: Potential Anticancer Agents. Retrieved October 10, 2010, from http://www.brainlife.org/reprint/2003/guzm%C3%A1n_m031000.pdf Luciano De Petrocellis, D. M. (1998, July 7). The endogenous cannabinoid anandamide inhibits human breast. Retrieved October 9, 2010, from PNAS: http://www.pnas.org/content/95/14/8375.full.pdf+html Maurizio Bifulco, C. L. (2006). Cannabinoids and cancer: pros and cons of an antitumour strategy. British Journal of Pharmacology, 123-135. Miles Herkenham, A. B. (1990). Cannabinoid Receptor Localization in the Brain. Retrieved October 8, 2010, from PNAS: http://www.pnas.org/content/87/5/1932.full.pdf+html

N Olea-Herrero, D. V.-C.-L. (2009). Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R()-Methanandamide and JWH-015: Involvement of CB2. Retrieved October 9, 2010, from British Journal of Cancer: http://www.nature.com/bjc/journal/v101/n6/pdf/6605248a.pdf Robert J. McKallip, W. J. (2006, June 5). Cannabidiol-Induced Apoptosis in Human Leukemia Cells: A Novel Role of Cannabidiol in the Regulation of p22phox and Nox4 Expression. Retrieved October 12, 2010, from Molecular Pharmacology: http://molpharm.aspetjournals.org/content/70/3/897.full.pdf+html Robert Ramer, B. H. (2007, December 25). Inhibition of Cancer Cell Invasion by Cannabinoids. Retrieved October 10, 2010, from http://jnci.oxfordjournals.org/content/100/1/59.full.pdf+html Sami Sarfaraz, F. A. (2005, March 1). Cannabinoid Receptor as a Novel Target for the Treatment of Prostate Cancer. Retrieved October 11, 2010, from Cancer Research: http://cancerres.aacrjournals.org/content/65/5/1635.full.pdf+html Sami Sarfaraz, F. A. (2007, December 22). Cannabinoid Receptor Agonist-induced Apoptosis of Human Prostate Cancer Cells LNCaP Proceeds through Sustained Activation of ERK1/2 Leading to G1 Cell Cycle Arrest. Retrieved October 11, 2010, from Journal of Biological Chemistry: http://www.jbc.org/content/281/51/39480.full.pdf+html Sullivan, J. M. (2000). Cellular and Molecular Mechanisms Underlying Learning and Memory Impairments Produced by Cannabinoids. Retrieved October 8, 2010, from CSH Press: http://learnmem.cshlp.org/content/7/3/132.full