January - February 2017 CNM by Cannabis Nurses Magazine

LIFESTYLES

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OPPORTUNITY

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EDUCATION January/February 2017

By: Carey S. Clark, PhD, RN- AHN-BC, RYT

By: Dr. Robert J. Melamede, PhD

By: Donald I. Abrams, MD

Carey S. Clark, PhD, RN - AHN-BC, RYT ACNA President-Elect

Medical Cannabis: The Healing Power of Knowledge

Editor’s Letter The beginning of the New Year 2017 is here! Many states this last legislative session passed medical and/or recreational cannabis legislation and we are coming of an age where the majority of the states now have medical cannabis programs and/or recreational programs. Cannabis is the hot topic of discussion and patients are more than ever integrating cannabis into their health and wellness. In this issue our main theme is on Oncology and Cannabis and the relevant articles to support your basic understanding as a Cannabis Nurse. We are honored to feature our main Cover Nurse from Maine, Carey S. Clark, PhD, RN-AHN-BC, RYT, who has written her article specifically for this issue on Oncology and Cannabis with her article, “Oncology and Early Palliation: The Role of Cannabis”. It is here where Aggarwal (2016) suggests that Nursing moves toward the term Cannabinoid Integrative Medicine (CIM) as a label to describe cannabis use in combination with traditional allopathic treatments and coining Cannabis Integrative Nursing (CIN) as supporting this newly emerging field. CIN would consider the whole person who is facing the oncological treatment process and palliation. We also included Dr. Clark’s article on “Advocacy, Activism, & Cannabis: One Nurses Journey & Suggestions”, which outlines a guide for Cannabis Nurses to model after. It is not easy for nurses to navigate in this newly developing field and she shares her wisdom and advice at the highest level of nursing. We also welcome and support her as she recently has become the President-Elect for ACNA taking office in January 2018. Congratulations Dr. Clark for leading by example! We then share an open letter written by, Dr. Robert Melamede on “Treating Children with Cannabis” which is a sensitive subject for parents who struggle with traditional treatments that are failing and are turning towards cannabis (both CBD: THC) as a natural and safe alternative despite its stigmas. Dr. Donald Abrams, then shares his article, “Cannabis & Cancer: Decoding the Connection” who provides a wealth of knowledge and expertise in his field of Oncology. One must also investigate international research and visit the works of Manuel Guzmán, PhD from Madrid who dives deeply into the science behind the plant on, “Cannabinoids: Potential Anticancer Agents” where he is known for laying the early groundwork in research on this very topic. Although lengthy, we felt its importance necessary in educating nurses with the basic foundation in cannabis and oncology with molecular levels of action at the cellular level. Lastly, we provide an introduction to our next issues Cover Nurse Anita Briscoe, MS, APRN-BC, who shares her “Introduction to Petition Letter: Adding Opiate Dependence as a Qualifying Condition in New Mexico”. Nurse Anita, is leading the way and a prime example on how one can add a qualifying condition to ones Medical Cannabis Program in their state. The full letter and bibliography will be published next issue. Stay tuned! Cannabis Nurses Magazine is also proud to announce our acceptance of the “Educational Achievement Award” awarded to Nurse Heather Manus RN at the Cannabis Business Awards 2016 on December 7th, 2016 in Denver, Colorado. We are so proud to have her achieve this accomplishment with such deserving nominees across the country. We believe in education and it is our duty to share this knowledge with the world. Thank you for your unconditional support in making this publication possible and continuing your subscription with Cannabis Nurses Magazine. Thank you for being the change. We must Grow. Julie Monteiro, RN, BSK “Ask Nurse Juhlzie” Editor@Cannabis Nurses Magazine

Contributors Heather Manus, RN January/February 2017

Publisher

Robert Herman/ND1Media

Managing Editor

Julie Monteiro, BSK, RN

Creative Director

Heather Manus, RN

Contributors Heather Manus, RN Sue DeGregorio-Rosen, RN Marcie Cooper, MSN, RN, AHN-BC Lisa Buchanan, RN ,OCN Jennie Stormes, BSN, RN Carey S. Clark, PhD, RN-AHN-BC, RYT Anita Briscoe, MS, APRN-BC Manuel Guzmán, PhD Dr. Robert Melamede Dr. Janet Sweeney Donald I. Abrams, MD Photography

Nelson Ramirez Morning Coffee Productions

Cannabis Nurses Magazine publishes the most recent and compelling health care information on cannabis health, studies, research, and professional nursing issues with medical cannabis. As a refereed, clinical practice bimonthly magazine, it provides professionals involved in providing optimum nursing care with the most up-to-date information on health care trends and everyday issues in a concise, practical, and easy-to-read format. Readers can view the magazine digitally for free online at: CannabisNursesMagazine.com or subscribe to a printed copy to be delivered to your door.

We are currently accepting articles to be considered for publication. For more information on writing for Cannabis Nurses Magazine, check out our writer’s guidelines at: cannabisnursesmagazine.com/writers-guidelines or submit your article to: editor@cannabisnursesmagazine.com 4780 W. Ann Rd., Suite 5 #420 N. Las Vegas, NV 89031 Editor@cannabisnursesmagazine.com Online 24/7 at: cannabisnursesmagazine.com

A native New Mexican and Registered Nurse specializing in all aspects of medical cannabis care. She is founder of the Arizona Cannabis Nurses Association and was honored for her efforts, and awarded the CannAwards “Best Charitable/Community Outreach Program", and Cannabis Business Awards “Activist of the Year 2015” and "Educational Achievement Award 2016". She believes cannabis is a gateway to health and will be a first-line medication of the future.

Sue Degregorio-Rosen, RN A pioneer activist and native of New Jersey, Sue lives in the lower Hudson Valley of New York State. She has held multiple positions in the administration of ER/Trauma/Burns throughout her 40 yr career. She is the legal liaison and associate editor for The National Cannabis Patients Wall. She is also an activist and a chapter leader for the 420 Seniors Network of NY and The Cannabis Nurses Network. Sue holds a certificate in Advanced Cannabis Nursing, lending her expertise to communities along the east coast.

Marcie Cooper, MSN, RN, AHN-BC

Marcie Cooper RN, MSN, AHN-BC is Board Certified as an Advanced Holistic Nurse and is working to build a bridge between conventional healthcare and holistic nursing care including cannabis therapeutics. She obtained education, certifications and training in various complimentary therapies including Hypnotherapy, Auricular Acupuncture, Healing Touch and Aromatherapy. She incorporates cannabis education with patients while working in hospice and palliative care throughout Colorado, and has witnessed the incredible benefits of cannabis.

Lisa Buchanan, RN, OCN

Lisa Buchanan is an Oncology Certified Nurse (OCN) in Washington state who has worked with the seriously ill and dying for more than 20 years. She a member of the Oncology Nurses Society (ONS), American Cannabis Nurses Association (ACNA), and the Washington State Nurses Association. She has earned certificates in the Core Curriculum for Cannabis Nursing and in the Advanced Curriculum for Cannabis Nursing through ACNA.

Jennie Stormes, BSN, RN

Jennie Stormes, RN, BSN lives in the state of Colorado, and formerly in both New Jersey and Pennsylvania, is a member of the ACNA, a board member of American Medical Refugees as Vice Chair, Colorado Springs Chair for CannaMoms, and a parent member of the Special Education Advisory Committee for Colorado School District 49 (Falcon). She specializes in Pediatrics and Neurology and has a passon for education.

Contributors

Contact Information Bio: Carey S. Clark, PhD, RN-AHN-BC, RYT Carey S. Clark, PhD has been a nurse for 22 years, with a wide practice background including experience within the acute care setting, pediatrics, hospice care, and parish nursing. Dr. Clark is an associate professor at University of Maine at Augusta and the President Elect for the American Cannabis Nurses Association (ACNA). She has worked closely with the ACNA and The Cannabis Medicine Institute to develop learning modules around the Endocannabinoid System. Having supported individuals on their healing journey with medicinal use of the sacred herb cannabis, Dr. Clark looks forward to sharing her knowledge with other like-minded nurses.

Bio: Donald Abrams, MD Donald I. Abrams, M.D. is chief of the Hematology-

Oncology Division at San Francisco General Hospital, an integrative oncologist at the UCSF Osher Center for Integrative Medicine and Professor of Clinical Medicine at the University of California San Francisco. He graduated from Brown University in 1972 and from the Stanford University School of Medicine in 1977. After completing an Internal Medicine residency at the Kaiser Foundation Hospital in San Francisco, he became a fellow in HematologyOncology at the UCSF Cancer Research Institute in 1980. During his fellowship, Dr. Abrams spent eight months working in the retrovirology laboratory of Harold Varmus, M.D. during the time that the first cases of AIDS were being diagnosed. He subsequently returned to the clinical arena where he was one of the original clinician/investigators to recognize many of the early AIDS-related conditions. He conducted numerous clinical trials investigating conventional as well as complementary therapies in patients.

Bio: Manuel Guzmรกn, PhD Manuel Guzmรกn was born in Madrid (1963) and took his BS (1986) and PhD (1990) in Biology from Madrid Complutense University. He is presently Full Professor of Biochemistry and Molecular Biology at that University. His PhD and postdoctoral research focused on the study of the regulation of liver and brain lipid metabolism. During the last dozen years he has been mostly involved in the study of how the active components of cannabis (the cannabinoids) act in the body, with special emphasis on the molecular mechanisms of that action and on understanding how cannabinoids control cell generation and death. This work has allowed characterizing new effects and signalling pathways evoked by cannabinoids, as well as putting forward new physiopathological implications derived from them.

Bio: Robert Melamede, PhD Dr. Robert Melamede has a PhD in Molecular Biology and Biochemistry from the City University of New York. Dr. Melamede retired as Chairman of the Biology Department at University of Colorado, Colorado Springs in 2005, where he continues to teach and research cannabinoids, cancer, and DNA repair. He is recognized as a leading authority on the therapeutic uses of cannabis, and has authored or co-authored dozens of papers on a wide variety of scientific subjects. Dr. Melamede also serves on the Editorial Board of The Journal of the International Association for Cannabis as Medicine, the Scientific Advisory Board of Americans for Safe Access, Sensible Colorado, Scientific Advisor for Cannabis Therapeutics as well as a variety other of state dispensaries and marijuana patient advocacy groups.

Publisher ND1Media Editorial Robert Herman

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We are honored to have Nurse Heather be awarded the 2016 Educational Achievement Award with the support of Cannabis Nurses Magazine. We are leading by example and could not be more proud. Thank you to all who support our mission and cause in educating the world one nurse at a time!

"Educational Achievement Award" Heather Manus RN Cannabis Nurses Magazine

Cannabis Business Awards 2016

January/February

Table of

2017

Contents 12

18 14

features 06: ONCOLOGY AND EARLY PALLIATION:

THE ROLE OF CANNABIS By: Carey S. Clark, PhD, RN- AHN-BC, RYT

12: TREATING CHILDREN WITH CANNABIS By: Dr. Robert J. Melamede, PhD

14: CANNABIS AND CANCER: Decoding the Connection

18:

By: Donald I. Abrams, MD

CANNABINOIDS: POTENTIAL ANTICANCER AGENTS By: Manuel Guzmán PhD

inside 16 | Introduction To Petition Letter: Adding Opiate Dependence as a Qualifying Condition in New Mexico By: Anita Willard Briscoe, MS, APRN-BC

17 | How to Talk to your Doctor 30 | Chef Herb & Cook with Herb 34 | CREATING HER-STORY! 36 | On Advocacy, Activism, and Cannabis: One Nurse’s Journey and Suggestions By: Carey S. Clark, PhD, RN- AHN-BC, RYT

Carey S. Clark, PhD, RN- AHN-BC, RYT A landmark study by Rowland, Schumann, and Hickner (2010) found that earlier initiation of palliative care lead to better outcomes for patients with aggressive non-small cell lung cancer. The oncology patients who received earlier palliation, defined as palliation initiated at onset of treatment (or in this case within 8 weeks of initial diagnosis), had higher quality of life scores, lower prevalence of depression, less aggressive care overall (including less futilely aggressive use of chemotherapy within the last two weeks of life), and an average increase of lifespan of over around 2.7 months compared to those who did not receive palliative care. While these patients were offered traditional forms of palliation, as cannabis nurses, we are called upon to explore the role of cannabis as a palliative medicine for people with aggressive and serious medical conditions. About 60% of all persons could benefit from palliation before they die, and yet many people do not receive palliation early in the course of their treatment (Aggarwal, 2016). Palliative care is a multi-disciplinary approach to providing impeccable symptom management and supportive care for patients and their families facing serious and potentially life-limiting illnesses. (Aggarwal). This paper will explore why cannabis should be included in palliative care efforts, and the role of the cannabis nurse in supporting oncology patientsâ&#x20AC;&#x2122; palliation through the use of cannabis.

Why Cannabis for Oncology Palliation?

The mainstream allopathic model of oncology care has historically failed to address the power of cannabis for palliation, but this is beginning to change as we move toward earlier palliation for patients. The Hospice and Palliative Nurses Association (HPNA) (2014) acknowledged that nurses must understand the evidence-base of medical use of cannabis and

January/February 2017 CANNABISNURSESMAGAZINE.COM

cannabinoids to treat patients who suffer from cancer, HIV, and cachexia. Furthermore, HPNA stated that hospice and palliative nurses should be providing their patients with information, evidence-based resources, and education around the use of cannabis to manage their symptoms. Of course the issue of educating folks around cannabis has some complexity, related directly to cannabis prohibition and the difficulty with researching cannabis as a cancer treatment and palliation option due to drug enforcement agency (DEA) schedule issues; this is more so true in the states where medical or recreational use remains prohibited. Preclinical evidence has suggested that cannabinoids in addition to palliation, enhance the anti-tumor activity of allopathic chemotherapeutic agents and decrease associated side effects, so the addition of cannabinoid-based preparations to standard cancer therapy should not be discouraged by treating oncologists (Abrams & Guzman, 2015). Cannabis nurses are likely aware that animal studies show cannabis holds great hope and promise for treating many types of cancer, from skin cancers to lymphomas and neoblastomas, we are also aware that cannabis can be used to support successful palliation for cancer patients regardless of the types of treatment they pursue (Hall, Christie, & Currow, 2005). One of primary roles as cannabis nurses needs to be that of empowering other nurses and providers to expand the knowledge base of how cannabis supports not only cancer treatment, but also more specifically palliation during oncological treatments. With the current concern about opioid use and addiction, even in palliation scenarios, cannabis may be a medicine of the future for supporting patients through serious medical crises.

Cannabinoid Integrative Medicine Aggarwal (2016) suggested that we move toward the term “Cannabinoid Integrative Medicine” (CIM) as a label used to describe cannabis use in combination with traditional allopathic treatments. Δ9Tetrahydracannabinol (THC) and other cannabinoids help to improve appetite, reduce nausea and vomiting, muscle spasms, cachexia, and alleviate severe pain (Aggarwal, 2016: Hall, Christie, & Currow, 2005). With nausea and vomiting, THC alone is fairly ineffective at controlling symptoms (think of the mediocre success of the synthetic version of THC, marinol, with chemotherapy associated symptoms) and we need to move toward whole plant preparations, as has been done in Canada. Although Canada allows for whole plant cannabis extract of 1:1 ration of Δ9-tetrahydrocannabinol-to-cannabidiol to be imported and utilized by pain patients, they also have stated that dried cannabis flowers are not an approved medicine. While this approach continues to distance patient-human from the source of healing, which is the cannabis plant itself, it also allows for cannabis to gain a perhaps more acceptable fit with the traditional allopathic approach to cancer and pain palliation. Several studies using a CIM model to palliation with oncology patients point toward success. A study in Israel demonstrated that medical cannabis use by 131 patients undergoing oncological treatment showed that over the course of the 8 week study, all cancer treatment related symptoms were improved including, nausea, vomiting, anorexia, weight loss, constipation, pain, and mood disorders (Bar-Sela et al, 2013). A retrospective study in Israel which examined 17,000 authorized medical cannabis oncology patients, found that they showed improvements in pain management (70% of patients), general well being (70% of patients), appetite (60% of patients), and nausea (50%) (Waissengrin, Urban, Leshem , Garty , & Wolf, 2015). Both of these studies contribute to our understanding of cannabis as an appropriate palliative medicine for oncology patients.

Spiritual Care and Suffering Aggarwal (2016) posited that use of cannabis and its associated feelings of euphoria, well-being, aversive memory extinction, sensory heightening, and spiritual insights could support those facing serious or life threatening illnesses and their associated treatments. We must also consider how CIM could address the psychological trauma associated with receiving a life-threatening or serious illness diagnosis. Heightened senses created by cannabis ingestion can facilitate the suffering patient into a hear-and–now presence, supporting the patient’s ability to enjoy the moment, enhance their knowledge of personal spirituality, and promote quality of life at the end of life (Aggarwal). The Nurses Emerging Role with Palliative Cannabis Integrative Medicine As cannabis nurses, we are called upon to both create and support the necessity of our call toward “every cannabis patient deserves a cannabis nurse”. What can nurses do to support patient’s palliative needs as they approach oncological treatments? The following outlines some basic ideas around CIM and palliation for cancer patients. Education Cannabis nurses need to educate themselves, other providers, and the populations we serve around how cannabis works, with particular consideration given to the needs of oncology patients’ care. Cannabis nurses need to acquire and refine their personal knowledge around the endocannabinoid system (eCS), endocannabinoid deficiency syndrome, and CIM as both a palliative tool and a potential treatment for cancer. Cannabis nurses need to have a level of comfort with discussing cannabis as a treatment and palliation option for oncology patients, and this begins with a movement toward finding safe palces in healthcare to speak knowledgably about cannabis without fear of losing our livelihoods. Cannabis nurses need to feel empowered to work as consultants with cancer and palliative care patients in the states where this activity is allowable. Cannabis nurses will generally have to seek cannabis education outside of mainstream academic settings, while also calling for our university and colleges to educate nurses and providers around the role of cannabinoids for treatment, healing, and wellness. January/February 2017 CANNABISNURSESMAGAZINE.COM

CIM-CIN, Palliation, and Holistic Modalities I have met many cannabis nurses who are interested in holistic nursing modalities, as we tend to recognize the body’s healing processes are complex. Holistic modalities such as yoga, meditation, and reiki help to decrease the stress response and support psychoneuroimmunological health, a requisite for all healing processes (Clark, 2014). Supporting patients’ ability to manage stress and lead a life of wellness is something that adds depth to CIM, or perhaps supports an emerging field of Cannabis Integrative Nursing (CIN). CIN would consider the whole person who is facing the oncological treatment process and palliation. In addition to supporting patients with proper cannabis use, providing evidence-based information about dosages, strains, and safe use of medicine, supporting their journey through kindness, caring, compassion and presence, the cannabis nurse is ultimately concerned with patients’ spiritual well being and supporting humans through and beyond their suffering. The practice of CIN would include use of holistic modalities to support patients’ total well being, including meditation, yoga, art therapy, aromatherapy, Reiki,Therapeutic Touch/ Healing Touch, massage, acupuncture, acupressure, shiatsu, herbalism, diet therapy, supportive exercise, being in nature, laughter therapy, guided imagery, progressive muscle relaxation, tai chi, qi gong, hypnotherapy, homeopathy, and movement therapies.

Cannabis Consciousness The cannabis nurse practicing CIN, in order to be effective with supporting palliation, will be comfortable with his/her own spirituality and will strive to support patients’ with their own spiritual growth and evolution. We must acknowledge the presence of a cannabis consciousness, and strive to better understand and explicate our human relationship with the sacred plant and it’s healing powers. Successful cancer treatment is related to a sense of emotional authenticity, and the cannabis consciousness can help to diminish negative outlooks, enhance optimismgratitude-happiness, release suppressed and repressed emotions, promote self-acceptance, overcome resistance to healing, and promote acceptance of the disease as a divine message to heal oneself (Bleshing, 2016).

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Carl Sagan (1971) wrote: “When I’m high I can penetrate into the past, recall childhood memories, friends, relatives, playthings, streets, smells, sounds, and tastes from a vanished era. I can reconstruct the actual occurrences in childhood events only half understood at the time. Many but not all my cannabis trips have somewhere in them a symbolism significant to me which I won’t attempt to describe here, a kind of mandala embossed on the high. Free-associating to this mandala, both visually and as plays on words, has produced a very rich array of insights.” The CIN role would support patients in undertaking this introspective type of work that supports healing on a deep, spiritual-consciousness level. Conclusion The realm of CIN and our role as cannabis nurses in oncology and palliative care is just now emerging. As we begin to move toward recognizing cannabis as an accepted medicine for supporting palliation during intense oncological treatments, let us not forget our role as truly holistic cannabis nurses. We can strive to ensure that every patient has not just a nurse to guide their cannabis journey, but a nurse who can support their total holistic healing, and, in concert with the sacred herb cannabis, ameliorate suffering and enhance evolution of the spirit.

References: Abrams, D.I. & Guzman, M. (2015). Cannabis in cancer care. Clinical Pharmacology Therapy, 97, 575-586. Aggarwal, S.K. (2016). Use of cannabinoids in cancer care: Palliative care. Current Oncology, 23 (Supp2), S33-S36. Bar-Sela, G., Vorobeichik, M., Drawsheh, S., Omer, A., Goldberg, V., &Muller, E. (2013). The medical necessity for medicinal cannabis: prospective, observational study evaluating treatment in cancer patients on supportive or palliative care. Evidence Based Complementary and Alternative Medicine, 1-8. doi: 10.1155/2013/510392.

www.naturalblaze.com

Bleshing, U. (May, 2013). Nine ways to deepen healing with cannabis and consciousness. Waking Times. Retrieved from http:// www.wakingtimes.com/2013/05/17/9-ways-todeepen-healing-with-cannabis-and-consciousness/ Clark, C.S. (2014). Stress, psychoneuroimmunology, and self-care: What every nurse needs to know. Journal of Nursing and Care, 3, 146. Hall, W., Christie, M., & Currow, D. (2005). Cannabinoids and cancer: Causation, remediation, and palliation. Lancet Oncology,6, 35-42. Hospice and Palliative Nurses Association. (2014). HPNA position statement: The use of medical marijuana. Retrieved from http:// hpna.advancingexpertcare.org/wp-content/ uploads/2015/08/The-Use-of-Medical-Marijuana.pdf Rowland, K., Schumann, S.A., & Hickner, J. (2010). Palliative care: Earlier is better. Journal of Family Practice, 59(12), 695-698. Sagan, C. (1971). Marijuanna Revisted. Retrieved from http://highexistence.com/carl-sagans-profoundessay-on-why-cannabis-consciousness-isdesperately-needed-in-this-mad-and-dangerousworld/ Waissengrin, B., Urban, D., Leshem, Y., Garty, M., &Wolf, I. (2015). Patterns of use of medical cannabis among Israeli cancer patients: A single institution experience. Journal of Pain Symptom Management, 49, 223â&#x20AC;&#x201C;230. doi: 10.1016/j.jpainsymman.2014.05.018

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An open letter from Dr. Robert Melamede - Dr. Janet Sweeney There is a factual basis fo the cannabis as therapy for a variety of childhood related illnesses. All humans have all of their body systems: cardiovascular, digestive, endocrine, immune, nervous, musculoskeletal, and reproductive; homeostatically regulated by the marijuana like compounds that we all produce, known as endocannabinoids â&#x20AC;&#x201C; cannabis from within. In fact, any time anyone on the planet gets hungry, it is because their brain made endocannabinoids that gives them the "munchies," just like consuming cannabis does. These facts were created not by medical cannabis advocates, but by millions of years of evolution. All living systems (a system is a collection of molecules) are flow dependent structures that only exists with the appropriate molecular and energetic inputs (food in the air) and outputs (waste removal) constantly occurring. In an ideal circumstance, the flows are balanced, homeostasis, in a fashion that promotes health. The flows are regulated by a combination of our genetics and our life's history. We all suffer from the common biochemical imbalance commonly called aging. However depending on subtle variations among individuals in our genetics, we are all more or less susceptible to a variety of disease states as we age. Because the Endocannabinoid System (eCS) regulates everything in our bodies, typically in a fashion that promotes health, manipulating the eCS offers unique opportunities to shift homeostasis in a multidimensional, holistic fashion to improve health. Historically, meaning since cannabis prohibition began in 1937,7,

January/February 2017 CANNABISNURSESMAGAZINE.COM

the major concern regarding the development of cannabis-based pharmaceuticals has been its psychological effects. These concerns, while applied to all, have been especially focused on children. Regardless of age, cannabis consumption has very different biochemical effects depending on the quantity consumed. For most people, low doses are euphoric. In contrast, high doses are dysphoric for most people. For many conditions, all that is required are low doses that provide therapeutic benefits, beyond making someone feel good. In contrast to the absurd position taken by our government, euphoria is good. Our Endocannabinoid System is the mind-body connection, and has been shown to be involved in the placebo effect. Therefore, manipulating the Endocannabinoid System has the capacity to enhance our health through our consciousness as well as directly affecting our body's biochemistry. With these facts in mind, it's the criminal absurdity that parents are put in the position of having to decide whether or not to break the law in order to see whether cannabis medicines might help a child suffering from terminal or intractable conditions such as cancer or seizures. There are many hundreds of peer-reviewed papers that demonstrate both the cancer killing properties of cannabinoids as well as their anti-seizure properties. The science supports the numerous anecdotal reports from parents whose children's lives have been saved or greatly enhanced as a result of treating terminal cancers with cannabis extracts (Rick Simpson Oil- RSO). Additionally, numerous lives that have been restored by ending hundreds of seizures that some children suffer on a daily basis, for example those suffering from Dravet's syndrome.

Unfortunately, cannabis is still not allowed in most Hospitals, Nursing Homes or Assisted Living Facilities, so these patients are limited on what they can use for symptom management, and are predominately limited to pharmaceuticals with side effects for managing their symptoms. What are the psychological effects of medicinal cannabis use, and how might they differ in adults versus children? Again, we must distinguish between high and low doses of cannabis medicines. For an adult, we know that low doses can be quite pleasant since relaxation, hunger, sensuality, introspection and sleep are promoted. In contrast, high doses of cannabis results in significant loss of ones normal mental control of emotions and intellect, often accompanied by intense visual hallucinations, fear and paranoia. As adults, can we understand the consciousness of young children, and how cannabis might impact it? This question becomes all the more pertinent when one considers a child that is suffering from hundreds of seizures a day, or one suffering from the consequences of debilitating radiation and chemotherapy. I think it is inappropriate to extrapolate the psychic effects of cannabis in adults to what may be occurring in children. In recent years, cannabis has been used to treat children suffering from seizures as well as those undergoing treatment for cancer. The children seem to adapt to the treatment easier than adults do. This observation implies something different is going on in their brains from what is occurring in adults. Nevertheless, various approaches have been developed in an effort to minimize the well-known psychic effects that cannabis produces in the adult brain.

For all but the diehard prohibitionists, there is a relatively simple solution for children suffering from seizures. High CBD extracts, produced from legal, certified, low THC hemp plants are very effective for children suffering from seizure disorders. The benefits of this treatment were recently dramatically demonstrated in the Sanjay Gupta special in which he apologized to the public for previously not having improperly researched the benefits of medical marijuana. This change was the result of him seeing for himself how profound cannabis therapy can be for seizures in children. For many adults, smoking cannabis has been very beneficial for controlling their seizures, especially when one is able to recognize that a seizure is about to occur. A seizure can often be prevented do to the rapid onset of effects that result from using the pulmonary route (smoking or vaporizing). One should keep in mind that there is a long term history of use of cannabis for seizure treatment, as well as many modern scientific articles that provide an understanding as to why cannabis has such beneficial effects on seizure disorders. In summary, depending the child, reasonable doses of non-psychoactive, high CBD medicine appears to be an effective treatments option of seizure disorders and has scientific, anecdotal, and historical support. Unfortunately, while there is significant scientific evidence from in vitro studies that high CBD extracts have cancer killing properties, the anecdotal data is not as encouraging as is seen with high doses of extract containing THC. Nevertheless, too many children run out of options for conventional cancer treatment due to the failure of these treatments to control the cancer. More and more desperate parents are turning to highdose, high THC containing cannabis extracts as a result of a few wellpublicized examples that clearly showed a prolongation and dramatic improvement of the quality of life for children suffering from terminal cancers such as glioma. Thankfully,

Dr. Janet Sweeney from the Phoenix Tears Foundation (http:// www.phoenixtearsfoundation.com) made the profound discovery that the use of citicoline (cytosine diphosphate choline), an over the counter nutraceutical, in conjunction with THC containing cannabis dramatically reduces the psychoactivity that would otherwise occur. The concurrent use of citicoline with THC containing extracts makes cannabis based cancer treatments dramatically more tolerable. Patients are able to reach the high doses necessary for cancer treatment more rapidly, and with dramatically reduced negative consequences. For those of us who have participated in the underground ambulance, we have no doubts that cannabis can be an effective treatment for numerous cancers in both children and adults. Like any other treatment, it does not work all the time, especially when a patient cannot tolerate high THC doses, or has been brought to the edge of death with conventional treatments. Personally, I have trouble understanding why anyone would be so concerned about the psychological effects of cannabis treatment when dealing with a terminal illness, be they children or adults. It's incredible to me that our government would deny a parent the right to choose cannabis therapy for an otherwise dying child. We see more and more parents moving to Colorado where they can legally get cannabis extracts rather than to exclude this treatment option as they fight for the life of their child. The federal government has spent millions of dollars of our tax money on both cancer and cannabis research. Yet, the results are ignored because of the incompetence of our legislators to properly investigate this controversial topic, and the fanatical obstructionism imposed by the DEA (http://www.youtube.com/watch? v=kFgrB2Wmh5s). Will we ever hear an apology from our legislators for the lives lost due to their incompetence as we did from an honorable person like Sanjay Gupta?

Dr. Robert J. Melamede, Ph.D. President/CEO Cannabis Science Inc. http://www.cannabisscience.com/ Dr. Robert Melamede Associate Professor and Biology Chairman (ret) Biology Department University of Colorado 1420 Austin Bluffs Parkway Science and Engineering Building Osborne Center, room 351 Colorado Springs, CO 80918 Source: FB Page: Rick Simpson December 2, 2013 â&#x20AC;˘ https://www.facebook.com/ ricksimpsonofficial/ posts/597100540337089 http:// www.phoenixtearsfoundation.com/ How much should a novice cancer patient starting out taking? You can take up to four (4) - 250mg capsules at a time (1 g/day) PRN (as needed) and up to twelve (12) a day. I usually start a person at one capsule (250mg) and go up as needed. For example: For an adult cancer patient, they can go up to 12/day X 250mg a day = 3g/day

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CANNABIS AND CANCER Decoding the Connection Donald I. Abrams, MD It seems like just yesterday that claims were being made that cannabis caused cancer. Epidemiologic reports suggested that regular cannabis use might be connected with the obvious head and neck malignancies and lung cancer, but also some that seemed more farfetched such as cervical, prostate, and testicular. Subsequent analyses called most of these associations into question. One data set from Kaiser Northern California suggested that cannabis use might actually decrease the risk of lung cancer, a finding supported by a later case-controlled investigation from the pulmonologist at UCLA who has spent forty years studying the potential adverse effects of cannabis on the lungs. Then came the report suggesting that cannabis might decrease the risk of bladder cancer. And now, as the pendulum continues to swing, suddenly we are faced with increasing claims being made that cannabis actually cures cancer. What is the origin of such a notion? The unearthing of the tomb of the Siberian Ice Maiden in 1993 revealed the well-preserved remains of a young woman presumed to have lived twenty-five hundred years ago. The maiden had metastatic breast cancer and was found buried with a pouch of cannabis, suggesting to the archeologists that she was using cannabis for symptom management as well as possibly a direct anti-cancer effect. Fast forward to 1974 when scientists at the National Cancer Institute published their findings that cannabinoids—delta-9-tetrahydrocannabinol (THC), delta-8-THC, and cannabidiol (CBD)—were all able to suppress the growth of Lewis lung adenocarcinoma cells in vitro and in mice. An increasing body of pre-clinical evidence from investigators predominantly in Spain and Italy supports the possibility of cannabinoids having anti-cancer effects, but to date there has only been one human study. Because the brain is enriched for the cannabinoid-1 receptor, it makes some sense that gliomas are a particularly responsive to the antineoplastic effects of cannabinoids. This led to a study conducted on patients with recurrent glioblastoma multiforme in the Canary Islands, where investigators applied topical delta-9-THC via a catheter directly into the tumors. The results were not impressive.

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Certainly it cannot be the underwhelming result of that single human trial that is fanning the flames of the “Cannabis Cures Cancer” movement. A Canadian boiler maintenance worker heard of the news that cannabis may suppress tumors in 1974, two years after a cousin had died an agonizing death from cancer. Thirty years later when he was dealing with three basal cell carcinomas, he decided to treat them with a highly concentrated cannabis oil preparation. When the lesions disappeared, the highly concentrated cannabis oil took on his name and, with the impact of social media, went viral so that people all over were seeking such preparations for topical treatment of skin cancers and subsequently oral ingestion for diverse malignancies. Patients posted radiographic evidence of their tumors shrinking or disappearing on the internet, and a mass movement had begun. Interestingly, a number of the most vocal advocates for the benefits of cannabis oil seem oddly amnesiac that they were also treated with chemotherapy or other conventional means.

As an oncologist in San Francisco for the past thirty-three years, I often say that I would venture to guess that the majority of the patients I have cared for have used cannabis during their treatment. Thus, if cannabis cured cancer, I would have a lot more survivors. Granted, the plasma concentration of inhaled cannabis, as most of my patients have likely used in the past, probably does not approach that which can be achieved with the highly concentrated oil preparations (no data available on this as yet), but still, oncologists maintain that the plural of anecdote is not evidence! What saddens and disturbs me the most is when I see a patient in consultation with a potentially curable malignancy who is foregoing conventional cancer therapy in hopes that cannabis oil will be a kindler, gentler treatment. The fact remains, there is no evidence at this time to support such a decision. Having completed a number of clinical trials investigating the effect of inhaled cannabis on the pharmacokinetics of protease inhibitors and sustained release opioids without seeing clinically significant perturbations of plasma concentrations of the pharmaceuticals, I hopefully extrapolate that the cannabis oil preparations will behave similarly. But again, the reality is that we have no such information. And if we were to study it, would we use a high THC oil, or a high CBD oil, or one that has one of the magic THC:CBD ratios touted by those who purvey them?

Having lived through the rise and fall of many “alternative” cancer cures during these past three-plus decades, I fear that cannabis may go the way of laetrile or shark’s cartilage, dismissed as bogus and fraudulent. The reality is that there is an increasing body of evidence that cannabinoids work against cancer cells from many angles—increasing apoptosis, decreasing angiogenesis through inhibition of vascular endothelial growth factor and thwarting invasion and metastases by matrix metalloproteinase-2. What is lacking is the demonstration that these in vitro effects translate into any benefit for people living with cancer. But there is a body of evidence that cannabis is an effective medicine for the management of symptoms arising from cancer or its treatment, so a blanket dismissal of cannabis as an invalid cancer treatment would deprive patients of a very valuable therapy.

Oncologists demand evidence before they embark on a therapeutic option. That makes sense because the diseases we treat and the interventions we employ are serious and potent, so data is essential before recommending any regimen. Similarly, one would hope to see data supporting the effectiveness of cannabis as an antiemetic, appetite stimulant, analgesic, sleep aid or mood elevator before feeling confident suggesting its use. It is important to recall, however, that the only legal source of cannabis for research in the United States is the National Institute on Drug Abuse (NIDA), and that they have a mandate from Congress to only study “substances of abuse” as substances of abuse and not therapeutic interventions. So if one wants to investigate the clinical effectiveness of cannabis as medicine, the drug can be obtained from NIDA, but funding must come from elsewhere. There are numerous additional regulatory hoops that must be surmounted before such a study can be conducted. Current data mainly involves the licensed delta-9THC product, dronabinol, which has been the most widely studied cannabinoid medicine in the U.S. Dronabinol was licensed and approved for treatment of chemotherapy-induced nausea and vomiting in 1986, so oncologists theoretically should have the most experience using cannabis-based medicines. The fact that the single most active component of the parent plant is available supports the observation that the botanical itself is a useful antiemetic. Many of us have patients who forego the use of prescription anti-nausea medications in favor of using cannabis alone.

In animal models, cannabinoids are effective in both treatment and prevention of peripheral neuropathy caused by each of the three main classes of chemotherapy associated with this vexing symptom - the vinca alkaloids, the platinums and the taxanes. A number of studies, including one we conducted in HIV-related peripheral neuropathy, have suggested that inhaled cannabis is effective in various neuropathic syndromes. Interestingly, all of these studies suggest that the number of patients needed to treat for one to have a benefit (NNT) is consistently between three and onehalf and four, which is identical to the NNT for gabapentin, one of the more widely used interventions for painful neuropathy. As yet, only one small study of an oromucosal spray preparation of whole cannabis extract has been completed in sixteen patients with chemotherapy-induced peripheral neuropathy with results that would support conducting a larger follow-on confirmatory trial.

Often cancer patients require opioid analgesics for management of pain. A small pharmacokinetic interaction study that we conducted found no significant alteration of plasma levels of sustained-release morphine or oxycodone when vaporized cannabis was inhaled three times daily. There was, however, a signal that pain relief may have been augmented. Animal studies support the synergy between cannabinoids and opioids in analgesia. This is another potential role for cannabis medicines in cancer patients.

Many patients are now seeking CBD-enriched preparations to avoid the psychoactivity associated with delta-9-THC. Although euphoria may be considered a side effect of cannabis use, I would not consider it an adverse experience. If I have one medicine that can decrease nausea and vomiting, enhance appetite, decrease pain, improve sleep and mood, I consider that to be a valuable intervention. Instead of writing prescriptions for five or six pharmaceuticals that could all interact with each other or the chemotherapy I prescribe, I can recommend one very safe botanical. On asking cancer patients “What brings you joy?” I am impressed by the number who answer that gardening does. It seems as if one is dying, or feels that a part of them has died, the ability to bring life out of the ground is a special gift. And if one can grow their own medicine, that is especially empowering. Donald I. Abrams, MD, is chief of Hematology-Oncology at Zuckerberg San Francisco General and a Professor of Clinical Medicine at the University of California San Francisco. He provides integrative oncology consultations at the UCSF Osher Center for Integrative Medicine. He has been conducting clinical research with medicinal cannabis since 1997.

Selected References

1. Abrams, D.I. “Integrating cannabis into clinical cancer care.” Current Oncology 2016; 23:S8-S14. 2. Abrams, D.I. and Guzman, M. “Cannabis in Cancer Care.” Clin Pharm and Ther 2015; 97:575-586. 3.. wles, D.W., O’Bryant, C.L., Camidge, R., Jimeno, A. “The intersection between cannabis and cancer in the United States.” Crit Rev Oncol Hematol 2012; 83:1-10. 4.. Ca arel, M.M., Andradas, C., Pérez-Gómez, E., Guzmán, M., Sánchez, C. “Cannabinoids: a new hope for breast cancer therapy?” Cancer Treat. Rev 2012; 38, 911-918. 5. Guindon, J., Hohmann, A.G. “The endocannabinoid system and cancer: therapeutic implication.” Br. J. Pharmacol. 2011; 163, 1447–1463. 6. Health Canada. “Marihuana (Marijuana, Cannabis): Dried plant for administration by ingestion or other means.” Ottawa, Canada: Health Canada, 2010. http://www.hc-sc.gc.ca/dhpmps/marihuana/med/infoprof-eng.php. 7.. ht ://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional. 8.. Pisanti, S., Pic di, P., D’Alessandro, A., Laezza, C., Bifulco,

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Bio: Anita Willard Briscoe, MS, APRN-BC

Introduction To Petition Letter: Adding Opiate Dependence as a Qualifying Condition in New Mexico My mother came to Espanola, NM in 1952 to be a missionary nurse. At that time Espanola was a beautiful, bucolic village along the river, in the foothills of both the Jemez and the Sangre de Cristo mountain I ranges. It was a beautiful place to grow up.

Anita Willard Briscoe, is from New Mexico, and has been a Nurse for 40 years. She has been a psychiatric nurse for 24 years, and a psychiatric nurse practitioner for 12 years. She has her BSN, her Masters of Science in Community and School Health Education, and her Masters of Science in Psychiatric Nursing from University of New Mexico. She currently has her own private practice in Albuquerque where she refers her patients to the New Mexico Department of health Medical Cannabis Program, and is active in getting Opiate Dependence approved as a qualifying condition for medical cannabis.

I followed in my Mom’s footsteps and also became a nurse 40 years ago. Psychiatric nursing is my specialty, and for the past 7 years I have slowly given up prescribing pills and have been referring patients to our state’s cannabis program. Over these years, I started noticing my patients tell me, independent of each other, that they were able to quit heroin using cannabis. My colleagues agreed with me. For 4 months, I started to perform a literature review, and discovered there is indeed enough research now to be able to petition our Department of Health to add Opiate Dependence as a qualifying condition for cannabis. The research is showing that not only is cannabis replacing opiates for treatment of pain, it is being shown to occupy the same receptors in the brain as opiates. As the research continues to be developed and published, I will be focusing on how cannabis can replace opiates for pain, withdrawal, craving symptoms, as well as maintenance of sobriety. Espanola is now ravaged by heroin. It started with the Lowrider culture, and worsened when the Viet Nam Vets started coming back from the war. Espanola is now in a state of destruction and decay that is shocking to anyone who drives through it. Boarded up buildings, closed businesses, graffiti and trash everywhere. The homelessness, unemployment and poverty rates are among the highest in the nation. Our town’s opiate overdose death rate is rated second in the US. In November, 2016, the Medical Cannabis Medical Advisory Board approved my petition. As of December, 2016, it has to go to the Secretary of Health to sign of. If she signs this, New Mexico will be the first state, to allow the legal use of cannabis to quit opiates. Let us hope that our Secretary of Health approves this innovative, successful method of harm reduction. Nurses are at the forefront of cannabis treatment. We are on the ground, in the trenches, advocating for our patients who often do not have a voice, are disempowered and disenfranchised. Psychiatric nurses should be activists for their mentally ill patients, whether they have an organic disease or the disease of addiction. Cannabis has so much potential for treatment of addiction. We need to fight for the right to treat our patients with what has been proven to work.

What you as a Nurse can do in your state.

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The full petition letter to the NM Medical Advisory Board, Petition to the NM Medical Advisory boart to the New Mexico Medical Cannabis Program to Add Opiate Dependence as a Qualifiying Condition, will continue as our main featured Cover Nurse Story in our March/April 2017 Issue. Stay tuned!

How to Talk to Your Doctor About Medical Cannabis

Many people in Canada live with chronic diseases and symptoms that have been resistant to traditional medications and non-pharmaceutical approaches. An increasing number of people living with unresolved symptoms are looking for alternative solutions to improve their quality of life and cannabis is increasingly being considered. Because the only way to access medical cannabis legally in Canada is through the MMPR system with a “medical document” (aka “prescription”) signed by their doctor, this necessitates a conversation that can sometimes be difficult. Here are some tips that may help you and your physician if you want to consider medical cannabis and cannabinoids as a therapeutic option.

Speak up: Medical cannabis and pharmaceutical cannabinoids are a relatively new treatment option on the Canadian landscape. Most physicians will not think of this class of medication as they are not familiar with it (only ~ 10% of doctors have prescribed medical cannabis in Canada). Don’t be afraid to bring up the subject for fear of thinking “my doctor would never consider this” – you might be surprised! Physicians are

often willing to try new treatment options, especially if your medical condition has been particularly difficult to treat.

Be Honest: If you have used cannabis in the past and had a positive response, be prepared to talk about this with your doctor. Tell your doctor how this medication works for you, how it is different from other medications that you have used in the past, and why you would like to continue to use it in the future. One of the most powerful tools that you can do is to explain how cannabis improves your quality of life and allows you to be more functional. If accessing a legal, reliable and consistent source of medicine is important to you then bring this up as well.

Be prepared: Because physicians try to base their decisions on scientific evidence it is useful to come with studies to support the use of cannabis in your particular condition. If you bring in clinical studies or research that supports the use of cannabis in your condition this will demonstrate your commitment to exploring alternative solutions. Some excellent online resources include: Information for Health Care Professionals:

www.hc-sc.gc.ca/dhp-mps/ marihuana/med/infoprof-eng.php, The Canadian Consortium for the Investigation of Cannabinoids: www.ccic.net and The International Association for Cannabinoid Medicine: www.cannabis-med.org/ studies/study.php

Listen: If your doctor is hesitant to support your use of herbal cannabis listen to their reasons – maybe there are other options that are more appropriate for your particular condition. Remember that your doctor is also your partner in health and s/he is as dedicated as you are to allow you to lead the life you want to lead. If cannabis or cannabinoids may help you achieve your goals then chances are they will be open to having this conversation. Good Luck! Author: Danial Schecter Dr. Danial Schecter is the co-founder and medical director of the Cannabinoid Medical Clinic (www.cmclinic.ca). He has helped thousands of patients decide if cannabinoids are right for them and has educated thousands of doctors on the therapeutic potential of herbal cannabis.

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CANNABINOIDS: POTENTIAL ANTICANCER AGENTS Manuel Guzmán, PhD Cannabinoids — the active components of Cannabis sativa and their derivatives — exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies. So, could cannabinoids be used to develop new anticancer therapies? CANNABINOIDS

Compounds with tetrahydrocannabinol (THC)-like structures and/or THC-like pharmacological properties. Many compounds with a THC-like structure are present in cannabis, but not all of them have THC-like pharmacological properties. In addition, some natural or synthetic compounds have THC-like pharmacological properties but not THC-like structure.

CANNABIMIMETIC

Tetrahydrocannabinol (THC)-like in pharmacological terms. A compound is usually accepted as cannabimimetic if it produces four characteristic THC effects in an in vivo assay known as the ‘mouse tetrad model’: hypomotility, hypothermia, analgesia and a sustained immobility of posture (catalepsy).

Preparations from Cannabis sativa have been used for many centuries both medicinally and recreationally. However, the chemical structure of their unique active components — the CANNABINOIDS — was not elucidated until the early 1960s. As they are highly hydrophobic, cannabinoids were initially believed to mediate their actions by inserting directly into biomembranes. This scenario changed markedly in the early 1990s, when specific cannabinoid receptors were cloned and their endogenous ligands were characterized, therefore providing a mechanistic basis for cannabinoid action. This led not only to an impressive expansion of basic cannabinoid research, but also to a renaissance in the study of the therapeutic effects of cannabinoids, which now constitutes a widely debated issue with ample scientific, clinical and social relevance. The scientific community has gained substantial knowledge of the palliative and antitumour actions of cannabinoids during the past few years. However, further basic research and more exhaustive clinical trials are still required before cannabinoids can be routinely used in cancer therapy.

Cannabinoids and their receptors

Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain. e-mail: mgp@bbm1.ucm.es doi:10.1038/nrc1188

The hemp plant Cannabis sativa produces over ~60 unique compounds known as cannabinoids. Although the pharmacology of most of the cannabinoids is unknown, it is widely accepted that ∆9tetrahydrocannabinol (THC) is the most important, owing to its high potency and abundance in cannabis1. Other relevant plant-derived cannabinoids include ∆8-THC, which is almost as active as ∆9THC

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but less abundant; cannabinol, which is produced in large amounts but is a weak CANNABIMIMETIC agent; and CANNABIDIOL which is abundant but has no cannabimimetic activity. THC exerts a wide variety of biological effects by mimicking endogenous substances — the endocannabinoids anandamide and 2arachidonoylglycerol — that activate specific cannabinoid receptors (BOX 1). So far, two cannabinoid-specific receptors — CB1 and CB2 — have been cloned and characterized from mammalian tissues2. Both the central effects and many of the peripheral effects of cannabinoids depend on CB1-receptor activation. Expression of this receptor is abundant in the brain, particularly in discrete areas that are involved in the control of motor activity (basal ganglia and cerebellum), memory and cognition (cor-tex and hippocampus), emotion (amygdala), sensory perception (thalamus), and autonomic and endocrine functions (hypothalamus, pons and medulla), but the CB1 receptor is also expressed in peripheral nerve terminals and various extraneural sites such as the testis, eye, vascular endothelium and spleen. By contrast, the CB2 receptor is almost exclusively expressed in the immune system, both by cells, including B and T lymphocytes and macrophages, and by tissues, including the spleen, tonsils and lymph nodes2–4. Other than the endocannabinoids, there are three main structural classes of cannabinoid-agonist ligands. These are the ‘classical’ cannabinoid analogues of THC, the ‘non-classical’ bicyclic and tricyclic cannabinoid analogues of THC, and the aminoalkylindoles. All have

Summary •

•

Cannabinoids, the active components of Cannabis sativa and their derivatives, act in the organism by mimicking endogenous substances, the endocannabinoids, that activate specific cannabinoid receptors. Cannabinoids exert palliative effects in patients with cancer and inhibit tumour growth in laboratory animals. The best-established palliative effect of cannabinoids in cancer patients is the inhibition of chemotherapy-induced nausea and vomiting. Today, capsules of ∆9-tetrahydrocannabinol (dronabinol (Marinol)) and its synthetic analogue nabilone (Cesamet) are approved for this purpose. Other potential palliative effects of cannabinoids in cancer patients — supported by Phase III clinical trials — include appetite stimulation and pain inhibition. In relation to the former, dronabinol is now prescribed for anorexia associated with weight loss in patients with AIDS.

•

Cannabinoids inhibit tumour growth in laboratory animals. They do so by modulating key cell-signalling pathways, thereby inducing direct growth arrest and death of tumour cells, as well as by inhibiting tumour angiogenesis and metastasis.

•

Cannabinoids are selective antitumour compounds, as they can kill tumour cells without affecting their non-transformed counterparts. It is probable that cannabinoid receptors regulate cell-survival and cell-death pathways differently in tumour and non-tumour cells.

•

Cannabinoids have favourable drug-safety profiles and do not produce the generalized toxic effects of conventional chemotherapies. The use of cannabinoids in medicine, however, is limited by their psychoactive effects, and so cannabinoid-based therapies that are devoid of unwanted side effects are being designed. Further basic and preclinical research on cannabinoid anticancer properties is required. It would be desirable that clinical trials could accompany these laboratory studies to allow us to use these compounds in the treatment of cancer.

CANNABIDIOL

A non-psychoactive cannabinoid present in cannabis that inhibits convulsions, anxiety, vomiting and inflammation; it is now in Phase III clinical trials in combination with tetrahydrocannabinol for the treatment of multiple-sclerosisassociated muscle disorders.

been subjected to comprehensive structure–activity relationship studies, which, by selectively modifying the chemical structure of cannabinoid molecules, have led to the generation of various types of potent synthetic cannabinoid-receptor agonists. Selective cannabinoid-receptor antagonists such as the diarylpyrazoles (proto-typical compounds developed by Sanofi: for example, SR141716 for CB1 and SR144528 for CB2) have also been developed2,5. All of these compounds have been excellent pharmacological tools that have been used to achieve a detailed knowledge of cannabinoid action, and might serve as templates for the design of clinically useful drugs.

MYENTERIC AND SUBMUCOSAL PLEXUS

Palliative effects of cannabinoids

A network of sympathetic and parasympathetic nerve fibres and neuron cell bodies that are tucked in among the interstices of the smooth-muscle layer surrounding the digestive mucosa (myenteric plexus) or just underneath the digestive

Cannabinoids have been known to exert palliative effects in oncology since the early 1970s, and for this reason they are given to patients — although quite restrictedly — in the clinic. The molecular basis of the established and potential palliative applications of cannabinoids are still being dissected.

mucosa (submucosal plexus) and that coordinately control gastrointestinal contractions.

Inhibition of nausea and emesis. Prolonged nausea and emesis/vomiting is a devastating side effect that regularly accompanies the administration of cancer chemotherapeutic drugs. This unwanted effect can be so severe that some patients stop their treatments despite the persistence of malignant cancer. When nausea and vomiting are frequent, antiemetic drugs are routinely given before and after chemotherapy.

META-ANALYSIS

Statistical analysis of a large collection of results from individual studies for the purpose of integrating their findings.

Cannabinoids are antiemetic in animal models of vomiting6. As the CB1 receptor is present in cholinergic nerve terminals of the MYENTERIC AND SUBMUCOSAL PLEXUS of the stomach, duodenum and colon, it is probable that cannabinoid-induced inhibition of digestive tract motility is caused by blockade of acetylcholine release in these areas6. There is also evidence that cannabinoids act on CB1 receptors that are localized in the dorsal–vagal complex of the brainstem — the region of the brain that controls the vomiting reflex— and that endocannabinoids and their inactivating enzymes are present in the gastrointestinal tract and might have a physiological role in the control of emesis6,7. One of the earliest studied, and so far the best established, therapeutic benefits of cannabinoids in humans is the treatment of nausea and vomiting. A great number of clinical trials with THC, synthetic cannabinoids and cannabis smoking in the 1970s and 1980s showed that the antiemetic potency of cannabinoids was at least equivalent to that of the antiemetics widely used at that time, such as the dopamine D2-receptor antagonists prochlorperazine, domperidone and metoclopramide8–10. In addition, most of the patients tested had a clear preference for cannabinoids as antiemetics. META-ANALYSIS indicates that an optimal balance of efficacy and unwanted effects was achieved with relatively modest doses of THC (~5.0 mg/ day), and that the dose could be increased during chemotherapy cycles8–10. Today, capsules of THC (dronabinol (Marinol)) and its classical synthetic analogue LY109514 (nabilone (Cesamet)) are approved to treat nausea and emesis associated with cancer chemotherapy (TABLE 1). Nabilone also inhibits nausea and vomiting associated with radiation therapy and anaesthesia after abdominal surgery. However, the effect of nabilone in these treatments is moderate8–10. Although it is clear that cannabinoids serve as antiemetic agents in cancer therapy, several questions remain to be answered9. C annabinoids should be compared alone and in combination with modern antiemetics, such as the selective serotonin 5-HT3-receptor antagonist ondansetron and the selective substance P/neurokinin-1-receptor antagonist aprepitant, which have fewer associated side effects than the antiemetics that were used when the original cannabinoid trials were carried out. Of interest, cannabinoids are relatively effective in preventing nausea and emesis in patients during the delayed phase of chemotherapy-induced emesis, which usually occurs 24 hours or more after chemotherapy and is poorly controlled in about half of the patients receiving 5-HT3-receptor antago-nists6,7. The reason for this distinct behaviour of cannabinoids and 5-HT3-receptor antagonists is unknown, but might be because of the different pathophysiological bases of acute and delayed emesis. In addition, it is worth noting that cannabinoids can block 5-HT3 receptors 11. Further studies will be required to establish which patients and what types of cancer chemotherapy are suited to cannabinoid use for the prevention of nausea and emesis.

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Appetite stimulation. More than half of the patients with advanced cancer experience lack of appetite and/ or weight loss, and they consistently rank anorexia as one of the most troublesome symptoms. Anorexia might ultimately lead to massive weight loss — cachexia — which is an important risk factor for morbidity and mortality in cancer. About one-third of cancer patients lose more than 5% of their original body weight, and cachexia is estimated to account for ~20% of cancer deaths12.

and increase food intake in animals. These effects are particularly seen when cannabinoids are administered at low to moderate doses, which do not produce marked side effects13. The endogenous cannabinoid system might serve as a physiological regulator of feeding behaviour. For example, endocannabinoids and CB1 receptors are present in the hypothalamus, the area of the brain that controls food intake; hypothalamic endocannabinoid levels are reduced by leptin, one of the main anorexic hormones; and blockade of tonic endocannabinoid signalling with the CB1 antagonist

Many studies have reported that THC and other cannabinoids have a stimulatory effect on appetite Box 1 | The endogenous cannabinoid system

Plant-derived cannabinoids such as ∆9-tetrahydrocannabinol (THC), as well as their synthetic analogues, act in the organism by activating specific cell-surface receptors that are normally engaged by a family of endogenous ligands — the endocannabinoids (see figure). The first endocannabinoid discovered was named anandamide (AEA), from the sanscrit ananda,‘internal bliss’, and with reference to its chemical structure — arachidonoylethanolamide, the amide of arachidonic acid (AA) and ethanolamine (Et)100. A second arachidonic-acid derivative (2-arachidonoylglycerol (2AG)) that binds to cannabinoid receptors was subsequently described101,102. These endocannabinoid ligands, together with their receptors103,104 and specific processes of synthesis105,106, uptake107 and degradation108,constitute the endogenous cannabinoid system.

IONOTROPIC RECEPTORS

Channel-like receptors that are opened by agonist binding and through which ions such as Na+, K+ and/or Ca2+ can pass. Ionotropic glutamate receptors are usually divided into three groups: Nmethyl-D-aspartic acid (NMDA) receptors, kainate receptors and αamino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA) receptors.

A well-established function of the endogenous cannabinoid system is its role in brain neuromodulation. Postsynaptic neurons synthesize membrane-bound endocannabinoid precursors and cleave them to release active endocannabinoids following an increase of cytosolic free Ca2+ concentrations: for example, after binding of neurotransmitters (NTs) to their IONOTROPIC (iR) or METABOTROPIC (mR) receptors109. Endocannabinoids subsequently act as retrograde messengers by binding to presynaptic CB1 cannabinoid receptors, which are coupled to the inhibition of voltage-sensitive Ca2+ channels and the activation of K+ channels110. This blunts membrane depolarization and exocytosis, thereby inhibiting the release of NTs such as glutamate, dopamine and γ-aminobutyric acid (GABA) and affecting, in turn, processes such as learning, movement and memory, respectively111. Endocannabinoid neuromodulatory signalling is terminated by an unidentified membrane-transport system107 (T) and a family of intracellular degradative enzymes, the best characterized of which is fatty acid amide hydrolase (FAAH), which degrades AEA to AA and Et108. The endogenous cannabinoid system might also exert modulatory functions outside the brain, both in the peripheral nervous system and in extraneural sites, controlling processes such as peripheral pain, vascular tone, INTRAOCULAR PRESSURE and immune function. Plant-derived cannabinoid ∆9-Tetrahydrocannabinol (THC)

Presynaptic neuron

_ METABOTROPIC RECEPTORS

Seven-transmembrane (heptahelical) receptors that couple to heterotrimeric G proteins, thereby modulating pathways such as cyclic AMP–protein kinase A (via Gs or Gi), diacylglycerol– protein kinase C (via Gq) and inositol 1,4,5-trisphosphate–Ca2+ (via Gq). At least eight subtypes of glutamate metabotropic receptors are known.

↓Ca2+, K+ Endogenous cannabinoids

CB1

Anandamide (AEA)

2-Arachidonoylglycerol (2-AG)

O INTRAOCULAR PRESSURE

Pressure inside the eye. When it increases — for example, in glaucoma — damage to the optic nerve of the eye can result in blindness. Cannabinoids decrease intraocular pressure.

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AEA or 2-AG

O HO

Precursor

O OH

+ FAAH Et, AA Postsynaptic neuron

↑Ca2+

Table 1 | Palliative effects of THC and nabilone in cancer therapy Palliative effect on cancer therapy

Cannabinoid

Stage in clinical trials

References

Inhibition of nausea and emesis

THC, nabilone

Dronabinol and nabilone approved for cancer chemotherapy

Appetite stimulation

THC

Phase III with THC for cancer anorexia (however, dronabinol is approved for AIDS wasting syndrome)

Analgesia

THC

Phase III with THC for cancer pain

Inhibition of muscle weakness

THC, nabilone

Phase I/II with THC and nabilone for cancer depression and anxiety

Mood effects (sedation, antidepression, hypnosis)

THC (± cannabidiol) Not for cancer, but Phase III with THC for multiple sclerosis muscle-debilitating symptoms

6–10 8,10,13,18,19 21,22,24–26 8,10 7,28

THC, ∆9 -tetrahydrocannabinol

rimonabant (SR141716) — now in Phase III clinical trials for the treatment of obesity — inhibits appetite and induces weight loss13,14. Although the usual view is that cannabinoids centrally control appetite — as they are expressed in the brain — CB1 receptors present in nerve terminals15 and adipocytes16,17 might also participate in the regulation of feeding behaviour. Considerable anecdotal information from cannabis smokers and, more importantly, a series of clinical trials support the appetite-stimulating properties of THC8,10,13. In particular, the appetite-stimulating (orexigenic) action of THC has been repeatedly observed in AIDS patients, and so dronabinol is prescribed for anorexia associated with weight loss in AIDS patients (TABLE 1), at a dosage range of 2.5 – 5.0 mg/day8,10. In cancer patients, at least three Phase II clinical trials have established a relation between increased appetite and the prevention of body weight loss following THC treatment10,18, and a recent Phase III trial has confirmed the appetite-stimulating effect of oral THC at 5.0 mg/day in advanced cancer19.

NOCICEPTIVE

A stimulus that causes pain or a reaction that is caused by pain. HYPERALGESIA

An increased sensitivity and lowered threshold to a stimulus — such as burn of the skin —that is normally painful. ALLODYNIA

Pain caused by a stimulus — such as touch, pressure and warmth — that does not normally provoke pain.

Further research should elucidate the clinical relevance of cannabinoids for cancer anorexia. For example, the efficacy safety ratio of different regimens of cannabinoid administration should be evaluated in comparison with the progesterone derivative megestrol acetate, the most extensively used agent for treating cancer anorexia19. Moreover, cachexia is caused not only by depression of food intake, but also by increased energy wasting12. In this respect, it is interesting that the CB1 antagonist rimonabant not only suppresses appetite, but also enhances energy expenditure, indicating that CB1 activation could be involved in energy preservation16,17. Pain inhibition. Pain has a negative impact on the quality of life of cancer patients. Almost half of all patients with cancer experience moderate to severe pain, and it increases in patients with metastatic or advanced-stage cancer. Chronic cancer pain usually has a NOCICEPTIVE component, which originates from inflammatory reactions around the sites of injury, and a neuropathic component, which results from damage to the nervous system. So, the pharmacological management of chronic pain should target peripheral nerves, the spinal cord and the brain20.

Cannabinoids inhibit pain in animal models of acute and chronic HYPERALGESIA, ALLODYNIA and spontaneous pain, caused by heat, mechanical pressure, abdominal stretching, nerve injury and formalin injection21,22. There is sufficient evidence that cannabinoids produce antinociception by activating CB1 receptors in the brain (thalamus, periaqueductal grey matter and rostral ventromedial medulla), the spinal cord (dorsal horn) and nerve terminals (dorsal root ganglia and peripheral terminals of primaryafferent neurons), and that endocannabinoids function naturally to suppress pain by inhibiting nociceptive neurotransmission21,22. In addition, peripheral CB2 and/or CB2-like receptors might mediate local analgesia, possibly by inhibiting the release of various mediators of pain and inflammation21,23, which could be important in the management of cancer pain20. A meta-analysis of the clinical trials on cannabinoid analgesia is not feasible because of the dearth and heterogeneity of the trials carried out so far24. Nonetheless, there are some human data to support the effectiveness of cannabinoids in alleviating pain associated with cancer (TABLE 1), the effects of surgery, phantom limbs, multiple sclerosis, spinal-cord injury and migraine21,22. In particular, four Phase III clinical trials on cancer pain have been carried out, one with THC and the other three with two firstgeneration synthetic cannabinoid derivatives that are not used at present owing to their low potency and specificity. The general conclusion is that cannabinoids have similar analgesic potency to codeine — a moderate opioid analgesic24,25. Further clinical trials on cannabinoids in the treatment of cancer pain — including terminal care — seem justified24,26 and, in fact, are now in progress. An adjunctive role for cannabinoids in analgesia seems the most likely21,22 and, in this respect, it would be interesting to exploit the synergistic interactions that occur between cannabinoid and opioid antinociception observed in animal models21,27. Psychological effects. Studies in animal models indicate that cannabinoids — at least at low doses — exert anti-anxiety effects, and there is considerable anecdotal information about the effects of cannabis use on mood-related disorders4,10. However, only a few small trials with cannabinoids have systematically evaluated the mood

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Table 2 | Tumours that are sensitive to cannabinoid-induced growth inhibition Tumour type

Experimental system In vivo (mouse); in vitro

Effect Decreased tumour size; cell-growth inhibition

Receptor

Lung carcinoma Glioma

In vivo (mouse, rat); in vitro

Decreased tumour size; apoptosis

CB1, CB2

Thyroid epithelioma

In vivo (mouse); in vitro

Decreased tumour size; cell-cycle arrest

CB1

Decreased tumour size; apoptosis

CB2

96 61

Lymphoma/leukaemia

In vivo (mouse); in vitro

N.D.

References 29 50,51,53,85

Skin carcinoma

In vivo (mouse); in vitro

Decreased tumour size; apoptosis

CB1, CB2

Uterus carcinoma

In vitro

Cell-growth inhibition

N.D.

97,98

Breast carcinoma

In vitro

Cell-cycle arrest

CB1

57–59

Prostate carcinoma

In vitro

Apoptosis

CB1?

Neuroblastoma

In vitro

Apoptosis

VR1

54,59,99 51,73

N.D., not determined; VR1, type 1 vanilloid receptor.

state of cancer patients. THC and nabilone might lead to several positive psychological effects, including a reduction in depression and anxiety, which could result in improved sleep8,10 (TABLE 1).These potentially positive effects, which can influence the medical benefits, need to be objectively evaluated with further clinical trials. Inhibition of muscle weakness. Muscle weakness occurs in several chronic and debilitating neurological conditions such as multiple sclerosis and spinal-cord injury, and might also affect patients with cancer who have developed paraneoplastic syndromes such as SENSORY-MOTOR PERIPHERAL NEUROPATHIES and other MYASTHENIC syndromes. Increasing amounts of laboratory research and anecdotal information from cannabis users have led to Phase III clinical trials in which THC alone or in combination with other cannabinoids is being tested for treatment of spasticity and other muscle-debilitating symptoms of multiple sclerosis7,28 (TABLE 1).The potential applicability of cannabinoids to cancer-related muscle weakness is, as yet, unknown. SENSORY-MOTOR PERIPHERAL NEUROPATHIES

Diseases or abnormalities of the peripheral nervous system that affect senses and movement. MYASTHENIC

Abnormal muscle weakness or fatigue. FORKHEAD TRANSCRIPTION FACTORS

A family of proteins that regulate the expression of genes that are involved in the control of cell survival, death, growth, differentiation and stress responses. Their activity is tightly controlled by AKT, so that phosphorylated forkhead transcription factor FOXO is retained in the cytoplasm and remains transcriptionally inactive.

Antitumour effects of cannabinoids Inhibition of tumour-cell growth. The antiproliferative properties of cannabis compounds were first reported almost 30 years ago by Munson et al.29, who showed that THC inhibits lung adenocarcinoma cell growth in vitro and after oral administration in mice. Although these observations were promising, further studies in this area were not carried out until the late 1990s. Several plant-derived (for example, THC and cannabidiol), synthetic (for example, WIN-55, 212-2 and HU-210) and endogenous cannabinoids (for example, anandamide and 2-arachidonoylglycerol) are now known to exert antiproliferative actions on a wide spectrum of tumour cells in culture30 (TABLE 2). More importantly, cannabinoid administration to nude mice slows the growth of various tumour xenografts, including lung carcinomas, gliomas, thyroid epitheliomas, skin carcinomas and lymphomas.

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The requirement of CB1 and/or CB2 receptors for this antitumour effect (TABLE 2) has been shown by various biochemical and pharmacological approaches, in particular by determining cannabinoid-receptor expression and by using selective cannabinoid-receptor agonists and antagonists. In one study, endocannabinoids were suggested to exert their apoptotic effect by binding to the type 1 vanilloid receptor (VR1), a non-selective cation channel targeted by capsaicin, the active component of hot chilli peppers (TABLE 2). However, the precise role of this receptor in cannabinoid signalling is still unclear2. Possible mechanisms of antitumour action. Cannabinoids affect various cellular pathways by binding and activating their specific G-protein-coupled cannabinoid receptors. They inhibit the adenylyl cyclase–cyclic AMP (cAMP)–protein kinase A pathway and modulate the activity of Ca2+ and K+ channels2, which inhibits neurotransmitter release (BOX 1). Cannabinoids have also been found to modulate several signalling pathways that are more directly involved in the control of cell fate30: they stimulate mitogen-activated protein kinases (MAPKs) — the extracellular-signal-regulated kinase31,32 (ERK) and the stress-activated kinases JUN amino-terminal kinase (JNK) and p38 MAPK33–35 — which have prominent roles in the control of cell growth and differentiation36 (FIG. 1). Cannabinoid-induced MAPK stimulation has been observed in primary neural cells, neural cell lines, lymphoid cells, vascular endothelial cells and Chinese hamster ovary cells that were transfected with cannabinoid-receptor complementary DNAs. By contrast, cannabinoids have been found to attenuate ERK in a neuronal-like cell line in vitro37. Cannabinoid receptors are also coupled to stimulation of the phosphatidylinosi-tol 3kinase (PI3K)–AKT survival pathway38–40. Activated AKT can phosphorylate and inhibit nuclear translocation of FORKHEAD TRANSCRIPTION FACTORS41, thereby preventing the expression of pro-apoptotic proteins. Similar to ERK, the negative coupling of cannabinoid receptors to AKT has also been reported42. A role for PI3K as an upstream component of cannabinoid-induced ERK activation is seen in some systems43,44 but not in others45.

Cannabinoids Ca2+

CB1

VSCC SM

SMase

FAN

Gi/o

? Ceramide

Intracellular Ca2+ stores Ca2+ cAMP

De novo synthesis

ERK, JNK, p38

AKT

PKA

Control of cell fate

Figure 1 | Signalling pathways involved in the control of cell fate by cannabinoids. Cannabinoids exert their effects by binding to specific Gprotein-coupled receptors. The cannabinoid receptor CB1 signals several different cellular pathways. These include inhibition of the adenylyl cyclase (AC)–cyclic AMP–protein kinase A (PKA) pathway; modulation of ion conductances, by inhibition of voltage-sensitive Ca2+ channels (VSCC) and activation of Ca2+ release from intracellular stores; activation of mitogen-activated protein kinase cascades (extracellularsignal-regulated kinase (ERK), JUN amino-terminal kinase (JNK) and p38); activation of the phosphatidylinositol 3-kinase (PI3K)–AKT pathway; and ceramide generation, both acutely through FAN– sphingomyelinase (factor associated with neutral sphingomyelinase activation–SMase) and sustainedly through de novo synthesis. The crosstalk between the different pathways has been omitted for simplification.

Cannabinoids can modulate sphingolipid-metabolizing pathways by inducing sphingomyelin breakdown and acutely increasing the levels of ceramide46 — a lipid second messenger that can induce apoptosis and cellcycle arrest47,48. This effect is cannabinoid-receptor dependent but G-protein independent, and seems to involve the adaptor protein FAN (factor associated with neutral sphingomyelinase activation)49. Cannabinoidreceptor activation can also generate a sustained peak of ceramide accumulation through enhanced de novo synthesis42,50. Other targets for cannabinoids that might be involved in the control of cell fate include the transcription factor NF-κB and nitric-oxide synthase (NOS). However, the effects of cannabinoids on these two proteins are variable, ranging from activation to inhibition, and the underlying mechanisms of cannabinoid action remain obscure2.

PHEOCHROMOCYTOMA

A relatively severe tumour of adrenal-gland chromaffin cells that causes excess release of adrenaline and noradrenaline and is therefore characterized by hypertension and tachycardia.

Cannabinoids might exert their antitumour effects by several different mechanisms, including direct induction of transformed-cell death, direct inhibition of transformed-cell growth and inhibition of tumour angiogenesis and metastasis (TABLE 3). Cannabinoid-induced apoptosis can be exemplified by glioma cells51, in which apoptotic death depends on sustained ceramide generation50. The increased

ceramide levels observed in glioma cells after cannabinoid challenge would lead to prolonged activation of the RAF1– MEK–ERK signalling cascade50 and AKT inhibition42. It is generally accepted that ERK activation leads to cell proliferation; however, the relation between ERK activation and cell fate is complex and depends on many factors, one of which is the duration of the stimulus, as prolonged ERK activation can mediate cell-cycle arrest and cell death. Following cannabinoid-receptor activation, two peaks of ceramide generation are observed in glioma cells that have different kinetics (minute- versus day-range), magnitude (twofold versus fourfold), mechanistic ori-gin (sphingomyelin hydrolysis versus de novo ceramide synthesis) and function (metabolic regulation versus induction of apoptosis)52 (FIG. 2a).The apoptotic action of cannabinoids on glioma cells clearly depends on the second peak of ceramide generation and ERK activa-tion42,50,53. Pharmacological inhibition of de novo ceramide synthesis also prevents cannabinoid-induced death of prostate tumour cells54. The in vo lvement of oxidative stress55 and stressactivated protein kinases50,56 in cannabinoid-induced apoptosis can not be ruled out. CB1-receptor activation in breast carcinoma cells blocks the cell cycle at the G1–S transition57, and this has been ascribed to the inhibition of adenylyl cyclase and the cAMP–protein kinase-A pathway. Protein kinase A phosphorylates and inhibits RAF1, so cannabinoids prevent the inhibition of RAF1 and induce prolonged activation of the RAF1–MEK–ERK signalling cascade58. These signalling events mediate the antiproliferative action of cannabinoids on breast carcinoma cells by reducing the expression of two specific receptors, the high-molecularweight (100 kDa) form of the prolactin receptor and the high-affinity neurotrophin TRK recep-tor58,59. CB1receptor activation also induces cell-cycle arrest at the G1–S transition in thyroid epithelioma cells that are transformed with the KRAS oncogene both in vitro and in vivo60. The mechanism of cannabinoid action on the cell cycle remains to be established. Inhibition of growth-factor-receptor signalling following cannabinoid-receptor activation has also been observed in PHEOCHROMOCYTOMA37, skin carcinoma61 and prostate carcinoma54 cells, and could therefore constitute a general mechanism of cannabinoid antiproliferative action. However, its consequences on ERK activity are not obvious: for example, in pheochromocytoma cells, cannabinoids inhibit ERK37,whereas in breast carcinoma cells, cannabinoids activate ERK58. To grow beyond minimal size, tumours must generate a new vascular supply (angiogenesis) for purposes of cell nutrition, gas exchange and waste disposal — therefore, blocking the angiogenic process constitutes one of the most promising antitumour approaches now available62. Immunohistochemical and functional analyses in mouse models of glioma63 and skin carcinoma61 have shown that administration of cannabinoids turns the vascular hyperplasia that is characteristic of actively growing tumours into a pattern of blood vessels that is characterized by small, differentiated and impermeable capillaries.

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Table 3 | Possible mechanisms of cannabinoid antitumour action Process

Possible mechanisms

Induction of apoptosis

Ceramide accumulation by de novo synthesis; sustained ERK activation and AKT inhibition

References 42,50,53

Cell-cycle arrest

Adenylyl cyclase inhibition and sustained ERK activation? Inhibition of growth-factor-receptor signalling

57–59

Inhibition of angiogenesis Decreased expression of pro-angiogenic factors and metastasis and matrix metalloproteinases; inhibition of vascular-endothelial-cell migration and survival?

61,63,64

Ceramide (%)

400

300

200

100

0.1

Time (days)

b Glioma cell

Astrocyte

Cannabinoid CB1

↑ Ceramide

↓ AKT

↑ AKT

Apoptosis

Survival

Figure 2 | Differential cannabinoid signalling in transformed versus non-transformed glial cells. a | In glioma cells, cannabinoids can induce two peaks of ceramide (solid line). The short-term peak occurs through sphingomyelin hydrolysis and is not related to apoptosis. The long-term peak occurs by de novo ceramide synthesis, is involved in apoptosis, and does not occur in normal astrocytes or in glioma-cell clones that are resistant to cannabinoidinduced apoptosis (dashed line). b | In glioma cells, cannabinoid-induced ceramide accumulation inhibits AKT and induces apoptosis, whereas in normal astrocytes cannabinoids activate AKT and prevent ceramide-induced AKT inhibition, thereby promoting survival.

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This is associated with a reduced expression of vascular endothelial growth factor (VEGF) and other proangiogenic cytokines61,63,64, as well as of VEGF receptors (C. Blázquez and M.G., unpublished observa-tions). In addition, activation of cannabinoid receptors in vascular endothelial cells inhibited cell migration and survival, which might contribute to impaired tumour vascularization63. Administration of cannabinoids to tumour-bearing mice also decreased the activity and expression of matrix metalloproteinase 2 — a proteolytic enzyme that allows tissue breakdown and remodelling during angiogenesis and metastasis63. This might explain at least in part why cannabinoid-induced inhibition of tumour metastasis was observed in mice injected with lung carcinoma cells64. Selectivity of antiproliferative action. Antitumour compounds should selectively affect tumour cells. It seems that cannabinoids can do this, as they kill tumour cells but do not affect their non-transformed counterparts and might even protect them from cell death. The best characterized example is that of glial cells. Cannabinoids induce apoptosis of glioma cells in culture and induce regression of gliomas in mice and rats (TABLE 2). By contrast, cannabinoids protect normal glial cells of astroglial65 and oligodendroglial66 lineages from apoptosis. This protective effect is mediated by the CB1 receptor and the PI3K–AKT survival pathway. Cannabinoid-induced apoptosis of glioma cells is mediated by ceramide generation42,50; however, cannabinoids attenuate ceramide-induced apoptosis of normal astrocytes both in vitro and in vivo65. The molecular basis of this ‘ying–yang’ behaviour is not yet completely understood, but could result from the differential capacity of tumour and non-tumour cells to synthesize ceramide in response to cannabinoids52. As mentioned above, after cannabinoid-receptor activation two peaks of ceramide generation are observed in glioma cells, the second of which is due to enhanced de novo ceramide synthesis and triggers apoptosis. However, this second peak does not occur in normal astrocytes or in glioma-cell clones that are refractory to cannabinoidinduced apoptosis, despite the expression of functional cannabinoid receptors50,52 (FIG. 2a). Of interest, this resistance of primary astrocytes to cannabinoid-induced de novo ceramide synthesis and apoptosis is specific, as exposure of these cells to other stimuli such as uptake of the fatty acid palmitate67 or serum deprivation (A. Carracedo, M.G. & G.Velasco, unpublished observations) does induce apoptosis through de novo ceramide synthesis. It is therefore conceivable that cannabinoid receptors regulate cell survival and cell death differently in transformed and non-transformed cells. In glioma cells, cannabinoids inhibit AKT through ceramide42, whereas in primary astrocytes cannabinoids activate AKT and abrogate ceramide-induced AKT inhibition65 (FIG. 2b). The possibility that the ‘ying–yang’ action of cannabinoids depends on different patterns of cannabinoid-receptor expression and/or on the coupling of cannabinoid receptors to different types of G protein can not be ruled out.

Box 2 | Potential adverse effects of cannabinoids The administration of cannabinoids to humans and laboratory animals exerts psychoactive effects7,81,82. I n h u m a n s , cannabinoids induce a unique mixture of depressing and stimulatory effects in the central nervous system that can be divided into four groups: affective (euphoria and easy laughter), sensory (alterations in temporal and spatial perception and disorientation), somatic (drowsiness, dizziness and motor discoordination) and cognitive (confusion, memory lapses and difficulties in concentration). Owing to the ubiquitous distribution of cannabinoid receptors, cannabinoids might affect not only the brain, but also almost every body system; for example, the cardiovascular (tachycardia), respiratory (bronchodilatation), musculoskeletal (muscle relaxation) and gastrointestinal (decreased motility) systems7,81,82. The central and peripheral effects of cannabinoids are variable and sometimes pronounced in those smoking cannabis for recreational purposes, but are not necessarily apparent in a controlled clinical setting. In fact, dronabinol (Marinol) and nabilone (Cesamet) are usually innocuous when administered as antiemetics to patients with cancer10,82. M o r e o v e r , tolerance to the unwanted effects of cannabinoids develops rapidly in humans and laboratory animals81,82. F or example, the most frequently reported adverse psychoactive effects of dronabinol during clinical trials occurred in 33% of patients. This value decreased to 25% reporting minor psychoactivity after 2 weeks and 4% after 6 weeks of treatment. The possibility that tolerance also develops to therapeutically sought effects has not been substantiated. Cannabinoid tolerance is mainly attributed to PHARMACODYNAMIC changes, such as a decrease in the number of total and functionally coupled cannabinoid receptors on the cell surface, with a possible minor PHARMACOKINETIC component caused by increased cannabinoid biotransformation and excretion7,81,82. Some people consider cannabinoids as addictive drugs. A withdrawal syndrome, which consists of irritability, insomnia, restlessness and a sudden, temporary sensation of heat — ‘hot flashes’ — has been occasionally observed in chronic cannabis smokers after abrupt cessation of drug use. However, this occurs rarely, and symptoms are mild and usually dissipate after a few days7,81,82. S imilarly, after chronic tetrahydrocannabinol (THC) treatment, no somatic signs of spontaneous withdrawal appear in different animal species, even at extremely high doses112. A nimal models of cannabinoid dependence have been obtained only after administration of an antagonist of cannabinoid receptor CB1 together with the cessation of chronic administration of high doses of THC to precipitate somatic manifestations of withdrawal112. I n t he clinical context, long-term surveys of dronabinol administration at prescription doses have shown no sign of dependence82,113. The low-addictive capacity of THC is usually ascribed to its pharmacokinetic properties (BOX 3) as, unlike commonly used drugs, cannabinoids are stored in adipose tissue and excreted at a low rate. So, cessation of THC intake is not accompanied by rapid decreases in drug plasma concentration82.

However, this seems unlikely. On the one hand, glioma cell clones that are resistant to cannabinoid-induced apoptosis express similar amounts of CB1 and CB2 receptors, compared with cannabinoid-sensitive clones50; t h i s is further supported by pharmacological studies using selective cannabinoid-receptor antagonists50. O n the other hand, although activation of Gs proteins by the CB1 receptor has been reported68, increasing evidence indicates that cannabinoid receptors have a clear preference for coupling to Gi/o proteins2,69,70.

PHARMACODYNAMICS

Mechanisms by which drugs affect their target sites in the body to produce their desired therapeutic effects and their adverse side effects.

PHARMACOKINETICS

Time course of drug and metabolite levels in different fluids, tissues and excreta of the body, and of the mathematical relationships required to develop models to interpret such data.

Other reported examples of cannabinoid selectivity towards tumour cells include thyroid epithelioma60 and skin carcinoma61 cells. In addition, though perhaps mechanistically unrelated, cannabinoids protect neurons from death in various models of toxic damage7,71,72, w hereas neuroblastoma cells are sensitive to cannabinoid-induced death51,73. A possible exception to this cannabinoid selectivity might be immune cells, although this can depend on experimental conditions— mostly stimulus strength74. F or example, cannabinoids at high concentrations induce apoptosis of nontransformed monocytes, macrophages and lymhocytes75,76, w hich might contribute to impaired host antitumour responses by inhibiting the production of antitumour cytokines such as interferon-γ and inter-leukin-12 (REF. 77). B y contrast, low cannabinoid doses enhance lymphocyte78 and myeloid-cell growth79. I n any event, the issue of immunosuppression needs to be explicitly investigated in any trial of cannabinoids in cancer

patients80, although long-term surveys of HIV-positive patients have shown no link between dronabinol use or cannabis smoking and average T-cell counts or progression to AIDS8,10.

Towards the clinical application Side effects and how to circumvent them. Cannabinoids have a favourable drug safety profile8,81,82. Acute fatal cases due to cannabis use in humans have not been substantiated, and median lethal doses of THC in animals have been extrapolated to several grams per kilogram of body weight82. C annabinoids are usually well tolerated in animal studies and do not produce the generalized toxic effects of most conventional chemotherapeutic agents. For example, in a 2-year administration of high oral doses of THC to rats and mice, no marked histopathological alterations in the brain and other organs were found. Moreover, THC treatment tended to incease survival and lower the incidence of primary tumours 83. Similarly, long-term epidemiological surveys, although scarce and difficult to design and interpret, usually show that neither patients under prolonged medical cannabinoid treatment nor regular cannabis smokers have marked alterations in a wide array of physiological, neurological and blood tests8,10,82. The use of cannabinoids in medicine, however, is severely limited by their psychoactive effects (BOX 2). Although these adverse effects are within the range of

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Box 3 | Cannabinoid pharmacokinetics The route of administration affects the time course and intensity of the drug effects. At present, clinical use of cannabinoids is limited to oral administration of dronabinol and nabilone. However, absorption by this route is slow and erratic; cannabinoids might be degraded by the acid of the stomach; rates of FIRST-PASS METABOLISM in the liver vary greatly between individuals; and patients sometimes have more than one plasma peak, which makes it more difficult to control the drug effects82. Anecdotal reports indicate that in certain patients cannabis is more effective and might have fewer psychological effects when smoked than when taken orally. However, cannabis smoke contains the same chemical carcinogens that are found in tobacco, making it potentially harmful in long-term use and difficult to investigate in clinical trials80. A safer alternative for inhaled administration of cannabinoids has been recently produced by GW Pharmaceuticals and Bayer AG. This is a medicinal cannabis extract known as Sativex, which contains tetrahydrocannabinol (THC) and cannabidiol, that is administered by spraying into the mouth and is now in clinical trials for pain and the debilitating symptoms of multiple sclerosis. Other routes of cannabinoid administration tested so far in humans include intravenous (THC and dexanabinol in saline/ethanol/adjuvant), rectal (THC-hemisuccinate suppositories) and sublingual administration (THC- and cannabidiol-rich cannabis extracts)82. These three routes circumvent the aforementioned problems of oral administration by producing single, rapid and high drug-plasma peaks. Owing to its high hydrophobicity, absorbed THC binds to lipoproteins and albumin in plasma and is mainly retained in adipose tissue — the main long-term THC storage site. THC is only slowly released back into the bloodstream and other body tissues, so that full elimination from the body is slow (half-life 1–3 days). THC metabolism occurs mainly by hepatic cytochrome P450 isoenzymes. The process yields 11-hydroxy-THC and many other metabolites resulting from hydroxylation, oxidation, conjugation and other chemical modifications that are cleared from the body by excretion.

those accepted for other medications, especially in cancer treatment, and tend to disappear with tolerance following continuous use (BOX 2), it is obvious that cannabinoid-based therapies devoid of side effects would be desirable. FIRST-PASS METABOLISM

Pre-systemic metabolism of a drug that limits its exposure to the body. For example, chemical or enzymatic breakdown of a drug in the gastrointestinal lumen or in the stomach, intestine or liver cells can greatly reduce the amount of drug that ends up in the bloodstream.

DEXANABINOL (HU-211). A non-psychoactive

synthetic derivative of tetrahydrocannabinol that blocks ionotropic glutamate receptors and has antioxidant and antiinflammatory properties; it is now in Phase III clinical trials for the management of brain trauma.

AJULEMIC ACID (CT3). A synthetic derivative of the

tetrahydrocannabinol metabolite 11-carboxy-THC that inhibits pain and inflammation; it is entering Phase II clinical trials for the treatment of pain and spasticity in multiple sclerosis.

As the unwanted psychotropic effects of cannabinoids are mediated largely or entirely by CB1 receptors in the brain, a first possibility would be to use cannabinoids that target CB2 receptors. Selective CB2receptor activation in mice induces regression of gliomas53 and skin carcinomas61 and can also inhibit pain84 in the absence of overt signs of psychoactivity. Certain cannabinoids that act through non-cannabinoid receptors — and are therefore devoid of psychoactivity— would also be useful in cancer therapy. These include cannabidiol, which inhibits glioma-cell growth in vitro85,86, DEXANABINOL, o f w hich the effect on tumour-cell growth has not yet been tested71,87, and AJULEMIC ACID, w hich inhibits glioma-cell growth in vitro and in vivo88 — the pharmacological properties of ajulemic acid are, however, controversial88,89. Alternatively, the design of cannabinoids that do not cross the blood–brain barrier might exert antitumour, pain-killing and appetite-stimulating effects without causing psychoactivity. Another strategy would be to manipulate the effects of endocannabinoids. Achieving high endocannabinoid levels in the location of the tumour by selectively inhibiting endocannabinoid degradation has proved successful in animal models, as drugs that block anandamide breakdown exert antitumour effects with little psychoactivity90.

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Cannabinoids are poorly soluble in water, which determines their pharmacokinetic behaviour, in particular their poor bioavailability when given orally, and has been one of the difficulties in formulating preparations of pure compounds for medicinal use and for finding appropriate routes of delivery (BOX 3). In the case of a possible application in cancer therapy, it is conceivable that administration of a low dose of cannabinoid directly to the target site would increase effectiveness and reduce adverse side effects. So, using water-soluble cannabinoids — such as O-1057 —might help to overcome some of the pharmacokinetic peculiarities of cannabinoids5. Combined therapies. Cannabinoids should also be tested in combination with other chemotherapeutic drugs or radiotherapy to establish whether they can enhance present drug treatments. So far, only two such studies have been carried out. In one study, γ-radiation was found to increase cannabinoid-induced leukaemic cell death91. H owever, in the second study synergism was not observed between cannabinoids and tamoxifen during the induction of glioma-cell death85. I n any event, compounds that induce cell death through ceramide have proved useful in combined therapies92. F or example, fenretinide (N-(4hydroxyphenyl)retinamide) kills various types of tumour cell by enhancing ceramide synthesis, and this effect shows potent synergism with that of other compounds that raise intracellular ceramide levels93. S o, the usefulness of cannabinoids in combination therapy is still unclear. A pilot clinical trial. Glioblastoma multiforme, o r g r a d e IV astrocytoma, is the most frequent class of malignant primary brain tumour and is one of the most malignant forms of cancer. As a consequence, survival after diagnosis is normally just 6–8 months94,95. P r esent therapeutic strategies for the treatment of glioblastoma multiforme and other malignant brain tumours are usually inefficient and in most cases just palliative, and include surgery and radiotherapy. Some chemotherapeutic agents, such as temozolomide, carmustin, carboplatin and thalidomide have been tested and the most recent strategies for glioblastoma multiforme treatment are focused on gene therapy, but no trial carried out so far has been successful94,95. I t is therefore essential to develop new therapeutic strategies for the management of glioblastoma multiforme, which will probably require a combination of therapies to obtain significant clinical results. The Spanish Ministry of Health has recently approved a Phase I/II clinical trial, carried out in collaboration with the Tenerife University Hospital and my laboratory, aimed at investigating the effect of local administration of THC — as a single agent — on the growth of recurrent glioblastoma multiforme. This will be the first human study in which THC is administered intracranially through an infusion cannula connected to a subcutaneous reservoir. The clinical trial has just started, and it will be some time before the results can be determined. In the meantime, it is desirable that other trials —

on this and other types of tumours — are initiated to determine how cannabinoids can be used, other than for their palliative effects, to treat patients with cancer. Implications and future directions

One must be cautious when envisaging the potential clinical use of new anticancer therapies. Despite the huge amount of literature on how tumour cells work, there has been no parallel advance in the clinical practice of chemotherapy, and many compounds that inhibit tumour-cell growth in culture and in laboratory animals turn out to be disappointingly ineffective and/or toxic when tested in patients. Regarding effectiveness, cannabinoids exert notable antitumour activity in animal models of cancer, but their possible antitumour effect in humans has not been established. Regarding toxicity, cannabinoids not only show a good safety profile but also have palliative effects in patients with cancer, indicating that clinical trials with cannabinoids in cancer therapy are feasible.

As with many other antitumour agents, further research on cannabinoids is required and the precise mechanism of cannabinoid antitumour action needs to be clarified in more detail. If we can better understand the intracellular signalling pathways that are involved in cannabinoid antitumour action, determine which intercellular factors and processes (for example, angiogenesis and metastasis) are modulated by cannabinoids in tumours and which tumours are sensitive or resistant to cannabinoids and why, we will be one step closer to understanding how these compounds can be used in a clinical setting. Preclinical studies in animal models should also be carried out to optimize administration routes, delivery schedules, new ligands and adjuvants for potential cannabinoid therapies. As cannabinoids are relatively safe compounds, it would be desirable that clinical trials using cannabinoids as a single drug or in combined anticancer therapies could accompany these laboratory studies to allow us to use these compounds in the treatment of cancer.

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Acknowledgements I am indebted to all my laboratory colleagues, in particular to I. Galve-Roperh, G. Velasco and C. Sanchez for their continuous support and for making our research projects possible. This work was funded by ‘Fundación Científica de la Asociación Española Contra el Cáncer’ and ‘Ministerio de Ciencia y Tecnología’.

Online links DATABASES The following terms in this article are linked online to: Cancer.gov: http://www.cancer.gov/ Glioblastoma multiforme | breast cancer | leukaemia | lymphomas |lung cancer | prostate cancer | skin cancer | thyroid cancer LocusLink: http://www.ncbi.nih.gov/LocusLink adenylyl cyclase | AKT | CB1 | CB2 | EGF | ERK | FAAH | FAN | interferon-γ | interleukin-12 | JNK | KRAS | matrix metalloproteinase-2 | NF-κB | NGF | NOS | p38 MAPK | PI3K |RAF1 | VEGF FURTHER INFORMATION British Medical Association (therapeutic uses of cannabis): http://www.bma.org.uk/ap.nsf/Content/Therapeutic+uses+of+ca nnabis+-+%28m%29 GW Pharmaceuticals clinical trials: http://www.gwpharm.com House of Lords Committee on Science and Technology (therapeutic uses of cannabis): http://www.publications.parliament.uk/pa/ld200001/ldselect/ldsc tech/50/5001.htm | http://www.publications.parliament.uk/pa/ld199899/ldselect/ldsc tech/39/3901.htm | http://www.publications.parliament.uk/pa/ld199798/ldselect/ldsc tech/151/15101.htm International Cannabinoid Research Society: http://cannabinoidsociety.org IUPHAR Receptor Database: http://iuphar-db.org/iupharrd/index.html MRC multiple sclerosis clinical trial: http://www.cannabistrial.plymouth.ac.uk Pharmos (dexanabinol): http://www.pharmoscorp.com RxMed (nabilone): http://www.rxmed.com Sanofi–Synthelabo (rimonabant): http://www.sanofisynthelabo.com Unimed (dronabinol): http://www.marinol.com Access to this interactive links box is free online.

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~ All transdermal patches include an adhesive remover and alcohol swab ~ Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700785

"TDDS offer pharmacological advantages over the oral route and improved patient acceptability and compliance. They have been an important area of pharmaceutical research and development over the last few decades." -Oxford Journals Medicine &

Health

4 Different Varieties: Night Time Formula (40 mg THC) Crafted from high quality cannabis oil produced from Indica type varieties. May be used as a sleep aid, for mind and muscle relaxation, pain relief, or mood enhancement.

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CBD/THC Patch (1:1) (20/20 mg THC/CBD) Crafted from high quality cannabis oil produced from Hybrid type varieties and blended with high potency Hemp CBD to create a 1:1 ratio of 20mg CBD and 20mg THC, totaling 40mg per patch.

CBD Patch (40 mg CBD)* Crafted from high potency Hemp CBD and formulated to deliver a hefty 40mg dose of CBD. A rich source of antioxidant and neuroprotectant properties, Hemp CBD supports the eCB system and assists in obtaining and maintaining systemic wellness.

Rooted in ancient plant wisdom and expanded upon through science, Nature Nurse products support the endocannabinoid (eCB) system in balancing the mind, body, and spirit.

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January/February 2017 CANNABISNURSESMAGAZINE.COM

RASPBERRY VinAigREttE IngrEdIEnts -1- 12 oz. jar of raspberry puree -1 cup raspberry vinegar -1 Â˝ cup THC oil -1 squeeze lemon juice -Salt and Pepper to taste dIrECtIOns In a bowl, whisk raspberry puree with raspberry vinegar. Slowly drizzle in oil, continue to whisk until dressing looks shiny, about one minute. Whisk in lemon juice, salt and pepper. Make your own combination of greens and veggies, pour vinaigrette over salad.

PomEgRAnAtE SPinAch SAlAd IngrEdIEnts

-1 (10 ounce) bag baby spinach leaves, rinsed and drained -1/4 red onion, sliced very thin -1/2 cup walnut pieces -1/2 cup crumbled feta -1/4 cup alfalfa sprouts (optional) -1 pomegranate, peeled and seeds separated -Âź cup medicated balsamic vinaigrette dIrECtIOns Place spinach in a salad bowl. Top with red onion, walnuts, feta, and sprouts. Sprinkle pomegranate seeds over the top, and drizzle with medicated vinaigrette.

QuinoA cRAnBERRY SAlAd IngrEdIEnts -1 cup quinoa, rinsed and drained -2 cups water -1/2 cup chopped toasted pecans -1/2 cup dried cranberries -1/4 cup THC olive oil -2 tablespoons lemon juice -salt and pepper to taste

heat to medium-low, cover, and simmer until the quinoa is tender, and the water has been absorbed, about 15 to 20 minutes. Scrape into a mixing bowl, and cool to warm, about 20 minutes. Once the quinoa has cooled, stir in the pecans, cranberries, THC olive oil, and lemon juice; season to taste with salt and pepper to taste. Let stand at room temperature for 1 hour before serving.

gREEn SAlAd with PEARS And goRgonzolA IngrEdIEnts -1 head of butter lettuce (or Boston lettuce), cored, washed and dried and torn into bite-sized pieces -1/4 cup dried cranberries or cherries -1/3 cup crumbled gorgonzola cheese -2 pears, cored and sliced -1/2 cup candied pecans drEssIng -2 teaspoons whole grain mustard -2 tablespoons champagne vinegar (or red wine vinegar or balsamic) -1 tablespoon honey -1 tablespoon of minced shallot -1/3 cup THC olive oil -Pinch of salt and pepper dIrECtIOns Toss lettuce, cranberries or cherries, gorgonzola, pears and pecans in a large salad bowl. Set aside and prepare dressing. Alternately, set lettuce leaves on 6 salad plates, and top with cranberries or cherries, gorgonzola, pears and pecans. Place mustard in a medium-sized bowl. Whisk in vinegar, honey and shallot. Slowly drizzle in THC olive oil, while whisking constantly, to emulsify. Season with salt and pepper. Toss salad with half of the dressing (or drizzle over the plated salads). If more dressing is needed, add it a little at a time, taking care not to drench the leaves. Taste for seasoning and add more salt or pepper if needed. Serve immediately.

dIrECtIOns Bring the quinoa and water to a boil in a saucepan over high heat. Reduce

January/February 2017 CANNABISNURSESMAGAZINE.COM

cRown PoRk RoASt with APPlE cRAnBERRY Stuffing And PoRt winE SAucE IngrEdIEnts stUFFIng stUFFIng -Âź cup THC olive oil -3 onions, chopped -1/2 teaspoon ground cinnamon -1/2 teaspoon ground black pepper -1/4 teaspoon ground allspice -1 14- to16-ounce package of cornbread stuffing mix -1 cup pecans, chopped -3 apples cored, not peeled and chopped -1/2-cup fresh cranberries, chopped CrOWn rOAst -1 12 to16 rib crown pork roast -2 teaspoons salt -1 teaspoon ground black pepper sAUCE -1 cup chicken broth -1/4-cup port -3 tablespoon THC butter COOKIng InstrUCtIOns stUFFIng: In large skillet over medium heat, heat THC oil until shimmers. Add onions and cook about 6 minutes, stirring occasionally, or until translucent. Remove from heat and stir in cinnamon, pepper, and allspice to combine. In large bowl combine onions, stuffing mix pecans, apples, and cranberries. POrK rOAst: Heat oven to 350 degrees F. Sprinkle roast inside and out with salt and pepper. Add stuffing to inside cavity; do not pack it. Cook for about 2 hours 20 minutes, or until a thermometer in the thickest part of the meat registers 155 degrees. Remove from oven and cover with aluminum foil. Let rest at least 15 minutes. sAUCE: Place roasting pan over medium heat; add broth and port. Bring mixture to a boil, scraping up bits on the bottom of the pan. Reduce liquid by about half. Add THC butter and swirl to combine

January/February 2017 CANNABISNURSESMAGAZINE.COM

PEcAn cRunchY SAlmon IngrEdIEnts -3 tablespoons Dijon mustard -3 tablespoons THC butter, melted -5 teaspoons honey -1/2 cup fresh bread crumbs -1/2 cup finely chopped pecans -3 teaspoons chopped fresh parsley -6 (4 ounce) fillets salmon -salt and pepper to taste -6 lemon wedges dIrECtIOns Preheat the oven to 400 degrees F. In a small bowl, mix together the mustard, butter, and honey. In another bowl, mix together the bread crumbs, pecans, and parsley. Season each salmon fillet with salt and pepper. Place on a lightly greased baking sheet. Brush with THC mustard-honey mixture. Cover the top of each fillet with bread crumb mixture. Bake for 10 minutes per inch of thickness, measured at thickest part, or until salmon just flakes when tested with a fork. Serve garnished with lemon wedges. .

choco-PREtzEl StickS with A kick IngrEdIEnts -12 ounces white or semi-sweet or chocolate chips/melting disks -24 pretzel rods (8-oz. package) -4 tsp THC vegetable oil -2 cups of your favorite candy, nuts or topping -8 clear plastic bags -8 ribbons COOKIng InstrUCtIOns Line three baking sheets with wax paper and set aside. Melt chocolate over a double boiler or in the microwave. dOUBlE BOIlEr Place chocolate and THC vegetable oil in a heatproof bowl over a pot of simmering water. Water should barely simmer, not boil. Stir the chocolate frequently with a rubber spatula until melted, approximately 5 to 10 minutes.

MICrOWAVE Place chocolate in a microwave-safe bowl and microwave at 50 percent power for anywhere between 2 and 4 minutes (cook times vary with different models). Heat in 20-second intervals, stirring in between. Finish heating when most (but not all) of the chocolate is melted. Stir continuously until chocolate is smooth, shiny, and completely melted. Remove the bowls of melted chocolate from the double boiler/ microwave. Working in the chocolate bowl, dip in each pretzel. If the chocolate level is shallow, use a silicone pastry brush or rubber spatula to help smooth the chocolate over three-quarters of the pretzel. Be sure to leave a small portion of the pretzel uncovered by the chocolate to serve as the handle. Shake off excess chocolate so the pretzel has a thick – but not too thick – layer of chocolate. Place each dipped pretzel on a wax paper-lined baking sheet and sprinkle with your toppings. Refrigerate for 15 minutes or until chocolate is completely set. Gently peel the pretzel rods off of the wax paper and place 3 to 4 rods in each cellophane bag. Tie each with a ribbon and refrigerate until ready to give.

Almond ButtER cookiES IngrEdIEnts -Cooking spray -3/4 cup all purpose flour -1/2 cup whole wheat pastry flour, or regular whole wheat flour -3/4 teaspoon salt -1 teaspoon baking soda -1/4 cup unsalted THC butter, softened -3/4 cup smooth, unsalted almond butter -1/3 cup packed light brown sugar -1/3 cup granulated sugar -1/2 teaspoon vanilla extract -1 egg -36 raw whole almonds dIrECtIOns Preheat the oven to 375 degrees. Spray two baking sheets with cooking spray. In a large bowl whisk together the flours, salt and baking soda. In another large bowl beat together the THC butter, almond butter and sugars until fluffy. Add the vanilla and egg and beat until well combined. Gradually stir in the flour mixture, blending well. Shape the dough into 3/4 inch balls, and place on the baking sheets. Place an almond in center of each cookie and press down lightly. Bake for 10-12 minutes, until lightly browned. Cool on a wire rack.

tAStY thc PRAlinE cookiES IngrEdIEnts -8 ounces THC butter -1/2 cup light brown sugar, packed -2 teaspoons vanilla -2 cups sifted all-purpose flour -2 cups finely chopped pecans -sifted confectioners’ sugar, optional dIrECtIOns Cream THC butter and brown sugar; stir in vanilla. Gradually work in flour. Mixture will be crumbly. Add chopped pecans and work into dough. Pinch off dough and roll in hands to form balls about 1 inch in diameter. Place on greased baking sheets; bake pecan cookies at 325° for 15 to 20 minutes, until firm and browned on bottoms. If desired, roll pecan cookies in confectioners’ sugar while still warm.

tRAditionAl holidAY iRiSh cREAm (no thc) IngrEdIEnts -1 cup heavy cream -1 (14 ounce) can sweetened condensed milk -1 2/3 cups Irish whiskey -1 teaspoon instant coffee granules -2 tablespoons chocolate syrup -1 teaspoon vanilla extract -1 teaspoon almond extract dIrECtIOns In a blender, combine heavy cream, sweetened condensed milk, Irish whiskey, instant coffee, chocolate syrup, vanilla extract, and almond extract. Blend on high for 20 to 30 seconds. Store in a tightly sealed container in the refrigerator. Shake well before serving.

January/February 2017 CANNABISNURSESMAGAZINE.COM

CREATING HER-STORY!

Things are changing rapidly in the cannabis marketplace, with constant product innovation, improved standards and the emergence of brand building, professional marketing and public relations in the cannabis space. AK Ventures CEO, Kerri Accardi, knows medical cannabis is ready to go mainstream. Her new broadcast series, “Medical Cannabis: The Healing Power of Knowledge” is scheduled to debut this fall, supported by some of legal cannabis’ top new brands. With a passion for the plant, New York business savvy, and sheer determination, Accardi has forged partnerships with leading channels in every major U.S marketplace that, for the first time in history will allow cannabis brands to be seen on mainstream broadcast television. Each episode will contain segments covering areas of interest to viewers who may be learning the truth about cannabis for the first time. AK Ventures SPC is simultaneously launching an online media network called, ‘Hmm... Did You Know’ that will offer full series, bonus content, and cannabis industry commercials! www.hmmdidyouknow.com On HDYK, each series will be divided into ten episodes of 4:20, with two 15 second cannabis industry graphic commercials placed per episode. The intention is to create an alliance and education globally while taking the cannabis industry from virtually zero commercials to over 100, within 6 months professionally produced and placed in series “as seen on CBS”. Using the legacy of network television, AK Ventures intends to introduce cannabis as a beneficial plant to mainstream America. HDYK takes it global! Nurse Talk Hosts, RN Nurses Heather Manus and Nurse Juhlzie Monteiro, are leaders in the healthcare revolution, educating, and taking health back into their own hands after experiencing the Healing Powers of Cannabis first hand! “Nurse Talk” seeks to educate, inspire, and empower the masses through the healing power of Medical Cannabis. We will learn how cannabis works with our bodies, our endocannabinoid system, our cannabis receptors and the many mis-conceptions. Through interviews, exploration, product reviews and more we will learn from professional healthcare Nurses through their Patient and Professional POV’s. Fifth Quarter Marvin Washington, former NFL Superbowl Champion and staunch advocate for Cannabis takes on a tour of the Cannabis Industry, plant, and many components of the effect on athletes. Featuring Dispensaries, Labs, and Cannabis Businesses in an ESPN style series we will have interviews and discussions on the applications of cannabis in the treatment of athletic injuries and the many issues NFL Players experience. 420MEDIA was founded in 2014 specifically for the cannabis industry to showcase their brands and products through high end digital content, integrated marketing, advertising, PR and websites. www.420MEDIA.us

January/February 2017 CANNABISNURSESMAGAZINE.COM

ABOUT THE SERIES

Boo Williams, Nurse Heather Manus, and Juhlzie Monteiro, Marvin Washington, and Kerri Accardi

â&#x20AC;&#x153;The Healing Power of Knowledge" is a modern television variety show with a strong focus on information and educating viewers on the cannabis industry as a whole. The show will focus on topical discussions, interviews, product reviews, sports medicine, journalistic and political pieces about cannabis. Cannabis Nurses Heather Manus and Juhlzie Monteiro talk with military Veterans, Roger Martin and Michael Kravitz, about using cannabis to treat PTSD.

10.16 V2.2

Heather and Juhlzie share their educational conversation with the CannaMoms; a group dedicated to

raising awareness about the benefits of cannabis medicine for critically or chronically ill, medically-complex, and special needs children. The audience is introduced to the emotional story of 15- year old medical refugee and Crohnâ&#x20AC;&#x2122;s survivor / thriver, Coltyn Turner, and his family. Cannabis advocate and former NFL Star Marvin Washington tours a medical dispensary and shares his passionate belief that it is "time for cannabis to be looked at as a solution, not a problem."

Celebrity and athlete appearances are also in store as cannabis-savvy public figures stop by to show their support for cannabis education.

:30

30 minute episodes will premiere during primetime on Saturday evenings, with ten promotional spots airing the week leading up to each broadcast.

AK Ventures is producing each program and all promos independent of CBS. All programming will be vetted according to FCC regulations and CBS program guidelines.

On Advocacy, Activism, and Cannabis: One Nurse’s Journey and Suggestions By: Carey Clark, PhD, RN- AHN-BC, RYT

I am a Registered Nurse, an Associate Professor at the University of Maine, and an active ACNA member since 2014 and am the future President Elect of ACNA. Even though I have supported cannabis reform for many years this year brought me to a new point in commitment and with it came a lot of new perspectives. I was asked by the organizers of Yes on 1 to publicly voice my support for the “regulate and tax marijuana” measure. I read through the proposal several times and discussed it with those who support and oppose the measure. You see, I do not take lightly my decision to support Yes on 1 in Maine. I will say that I see it as an ethical obligation to talk about why I support both the medical use of cannabis (Maine’s medical program stays in place with Yes on 1) and the recreational use of cannabis. Yes on 1 asked me to write a letter about my stance that would go out to nurses from around the state of Maine. I was initially handed a form letter that a doctor had written. That would not work for me. I couldn’t sign onto something that was not in my voice and that did not directly speak to nurses. So I wrote my own and clarified why I think Yes on 1 should have the medical and nursing communites’ support. I focused on the Endocannabinoid System (eCS), safety and access for all cannabis users. I urged nurses to educate themselves about the eCS, and to consider the benefits for the state of Maine. I signed my name using my credentials, including that I am a board member of the ACNA and my title from the University of Maine. I feel compelled to note that had I not received tenure last year I likely would not have used my work title in the letter. I may not have even written the letter because the tenure process is a precarious one. I had some confidence knowing that I had earned my title, that I was exercising my right to freedom of speech, and I was not acting in a way that could lead to my dismissal (which can only be done through a long process of proving incompetence in the workplace). The letter emerged and was sent to random nurses around the state. I received one hateful email. “You should be ashamed of yourself, focusing on POT… shame on you…do something more useful with your PhD”. After I got over the shock I replied kindly, provided the sender with some links to my blogs that explain the eCS and ended with good wishes of peace and wellness. Meanwhile, I was unaware that people who received the letter were contacting my school — from my Dean to the President of the University! Nurses were asking my colleagues if they too supported Yes on 1 and some of my colleagues were upset. The President of the University was frightened of negative publicity and initially wanted to issue a statement that the letter contained only my views, not those of the university or university system. A colleague told me I had suffered an error in judgment and my stance might hurt our Nursing Department. The administration contacted the legal department to see what they could or should do about me (and my stance). My colleagues approached me before the school administration did and I can tell you I spent some time being fearful for my position. I contacted my union and asked for their thoughts and support. I called a lawyer for back up and spoke with the campaign about best tactics. Ultimately the school supported my right to free speech. University administrators offered suggestions for me about the letter (e.g., providing a disclaimer that the view were solely mine) and requested a courtesy heads-up about any future campaigning.

January/February 2017 CANNABISNURSESMAGAZINE.COM

The story doesn’t end here… the other day I received an email from a concerned medical cannabis patient in Arizona that had questions about my supporting their proposition in AZ. It turns out that my letter was, in part, utilized by the Arizona campaign though I had no knowledge of this. I truly have not studied whether Prop 205 is good for Arizona or not. I received an apology from the campaign, and a clear promise that they would contact me before using my name and credentials again without my permission. I do know there are several cannabis nurses in Arizona who support Prop 205 and I am sure some nurses do not as it has different restrictions than those in Maine’s Yes on 1. I share this last part of the story because I want Cannabis Nurses to be alert and active but also strong, wary, and safe. I want Cannabis Nurses to consider their own ability to stand up for this plant, whether that be medicinally or full legalization. I want you as a Cannabis Nurse and patient advocate to think carefully about your choices, to not be fearful of standing up and advocating for patients, populations, and the healing of the planet. Here are my recommendations for those who want to become more politically active in the cannabis arena:        

Know the issue at hand, study it closely and talk to the proponents and Work with the campaign or proponents. Be clear on what you are being asked to do. Learn as you go and keep on learning. Build your support system. Know your workplace and how they might react. Keep it clean and calm. Take care of yourself.

opponents. Editor’s Note: This article has been edited for

space considerations. To read the entire blog please visit The Nurse Doctor Carey.

If you are intuitive, tap into that power. It’s normal to feel anxious, scared or excited during a political process or when taking political action. It's also normal to feel empowered one day and worn out or defeated the next. Sometimes it’s normal to doubt or second guess yourself; this is where your support network becomes important. You need people who believe in you, who will help you feel your way through any anxiety or fear. Fill your spirit. Let it go and detach from the outcome. Do what you can and trust that you are guided on your path. Connect with the spirit and consciousness of the plant if you are able to do so. I would love to hear about your stories of advocacy and activism, and how the ACNA can support us in all our efforts toward getting patients the medicine they need.

January/February 2017 CANNABISNURSESMAGAZINE.COM

Apps for Health-Care Professionals Smartphone apps and web-based tools are increasingly important resources for health-care practitioners. Check out these great tools and put a wealth of health-care information in your pocket.

01 NURSING CENTRAL

06 EPONYMS

Nursing Central is the complete mobile solution for nursing produced by Unbound Medicine. The app includes disease, drug and test information for nurses. http://goo.gl/XWglb

A browse-able and searchable app that provides short descriptions of more than 1,700 obscure medical eponyms. http://goo.gl/BKP0H

02 LIPPINCOTT NURSING

07 NETTERâ&#x20AC;&#x2122;S ANATOMY FLASH CARDS

DRUG HANDBOOKS

Keep over 300 outstanding anatomical flash cards on your device. This app enables you to carry the popular Atlas of Human Anatomy (4th edition) and its detailed anatomical illustrations on your phone or tablet. http://goo.gl/jr9Th

This app provides up-to-date drug information on your device, including contraindications, nursing considerations, patient teaching and integration of the nursing process. http://goo.gl/em9E1

03 MANAGEMENT GUIDELINES FOR NUSING PRACTITIONERS WORKING WITH ADULTS The app is a best-practice guide for health-care professionals who work with adult patients. Other apps in the series provide guidelines for working specifically with women, with children, with older adults or in family practices. http://goo.gl/o2hC6

04 JOURNAL WATCH This tool from the Massachusetts Medical Society notifies you about new papers published on topics of your choice. http://goo.gl/dxbrd

05 3M PREP This app provides a detailed rationale for selecting surgical prep solutions. You can view how to correctly apply solutions while listening to a detailed set of instructions. http://goo.gl/QGwsY

08 CNOR EXAM PREP The Competency and Credentialing Institute, the governing body of the Certified Nurse Operating Room (CNOR) credentialing program, has created the CNOR exam prep app to help perioperative nurses prepare for the CNOR exam. The app helps individuals assess their exam readiness and develop critical thinking skills; it also provides tips for success, reviews knowledge related to the CNOR exam and can enhance test-taking confidence. http://goo.gl/n1DMo

09 EPOCRATES Rx The app includes a drug guide, formulary information and a drug interaction checker. This product also includes continual, free updates and medical news. Additionally, the app works on your device when you are offline, so you can look up information without a wireless connection. http://goo.gl/fqchG

10 MACEWAN LIB The MacEwan University Library app simplifies searches for books and articles. It allows you to place a hold on library catalogue items, renew items, download full-text resources and perform many other tasks. http://goo.gl/YAUQe

January/February 2017 CANNABISNURSESMAGAZINE.COM

Resources

Recommended Books

Hemp for Health: The Medicinal and Nutritional Uses of Cannabis Sativa Hemp, Cannabis sativa, is one of the world's oldest sources of food and medicine, with a history that dates back ten thousand years. It relieves glaucoma, epilepsy, migraines, insomnia, asthma, the nausea associated with AIDS and chemotherapy, and a host of other conditions. It was once a staple in every American medicine cabinet, but because hemp is the plant from which marijuana is derived, it has been unavailable to consumers until recently. Now products made from imported hempseed are sold by stores and mail-order companies across the United States to satisfy a growing demand. Hemp for Health reveals the developments that have returned this ancient plant to the forefront of health and nutrition and that have doctors calling for its legalization.

The Handbook of Cannabis Therapeutics: From Bench to Bedside (Haworth Series in Integrative Healing) The Handbook of Cannabis Therapeutics: From Bench to Bedside sets aside the condemnation and hysteria of societyâ&#x20AC;&#x2122;s view of cannabis to concentrate on the medically sound aspects of cannabis therapeutics. The worldâ&#x20AC;&#x2122;s foremost experts provide a reasoned, thoroughly researched overview of the controversial subject of cannabis, from its history as a medicine through its latest therapeutic uses. The latest studies on the botany, history, biochemistry, pharmacology, toxicology, clinical use for various illnesses such as AIDS, epilepsy, and multiple sclerosis, and side effects of marijuana are all examined and discussed in depth.

January/February 2017 CANNABISNURSESMAGAZINE.COM

Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential This comprehensive volume presents state-ofthe-art scientific research on the therapeutic uses of cannabis and its derivatives. All too often, discussions of the potential medical uses of this substance are distorted by political considerations that have no place in a medical debate.

Marijuana: The World's Most Misunderstood Plant By: Jeffrey Friedland

There never has been a plant as important to mankind, yet so misunderstood as marijuana. For at least 10,000 years it has been tied to human civilization. It was important as a source of fiber, as an herbal medicine, and yes, as a psychoactive substance. Marijuana: The Worldâ&#x20AC;&#x2122;s Most Misunderstood Plant explains why the plant affects us, its history, breeding, growing, and processing. The book describes how the plant is used today, from smoking to dabbing, from vaping to eating edibles. The book focuses on the huge potential for marijuana-based medicine and why it works to suppress pain, as an antiinflammatory, and for numerous diseases and conditions. For patients it provides a starting point in understanding why marijuana-based medicine may be beneficial as a treatment option.

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Cannabis Health & Wellness Education Pre-Conference Course & Event! 1st Annual Institute of Cannabis Research Conference - National Cannabis Nurses Lectures

April 27th, 2017 | Pueblo, CO

Lisa LeFevre RT(R), MBA

Julie Monteiro RN, BSK

Heather Manus, RN

Rawlings Library InfoZone Theater 100 E. Abriendo Ave. Pueblo, CO 81004

10:00am - 4:00pm Educational Course: Cannabis for Healing & Wellness

6:00pm - 8:30pm Cannabis Expo “Meet the Experts”

Featuring Heather Manus, RN: Lisa LeFevre RT(R), MBA: Julie Monteiro RN, BSK Agenda: • The Endocannabinoid System (eCS) • Methods of Administration • Terpenes & Aromatherapy • Touch Therapy • Wellness Perspective • Ending Prohibition- Our Ethnobiological Right *Limited to first 50 registrants **Lunch will be provided Bonus! Includes 1 year subscription to Cannabis Nurses Magazine

Meet and Speak with 12 professionals: • Cannabis Educators • Scientists • MDs • Nurses • Growers • Converters (MIPS) • Dispensaries • Testing Labs *Limited to first 50 registrants **Includes refreshments Produced and facilitated by Stonefield National (Lisa LeFevre)

Certificate Pricing (10am - 4pm): Earlybird (Dec-March) $269 Regular (April) $299 *Cash at the Door $320 Non-Certificate Pricing(10am - 3pm): Earybird (Dec-March) $240 Regular (April) $270 $290 *Cash at the Door

Tickets: Earybird (Dec-March) Regular (April) Cash at the Door

$64 $74 $84

Developed & Produced by:

For More Information Contact:lisa@stonefieldnational.com

Nursing Conferences Come meet the National Cannabis Nurses at these future Events!

2017

February 2017 Conferences

Women Grow Leadership Summit- National Cannabis Nurse Lectures "Modern Healing & Ancient Plant Wisdom" (Friday, Feb.3rd) February 1-3rd, 2017 | Denver, CO http://womengrow.com/summit/

March 2017 Conferences

Take Note

Cannabis Health & Wellness Education Event - National Cannabis Nurse Lectures March 2nd, 2017 from 6PM-9:30PM | Wellington, FL Stonefield National: lisa@stonefieldnational.com

Florida

April 2017 Conferences Pre-Conference Course & Event: Cannabis Health & Wellness - National Cannabis Nurse Lectures Course: April 27th, 2017 from 10AM-4PM and Event: 6PM-8:30PM | Pueblo, CO Stonefield National: lisa@stonefieldnational.com (see ad in this issue!) 1st Annual Institute of Cannabis Research Conference - National Cannabis Nurse Panel April 28th- 30th, 2017 | Pueblo, CO http://www.csupueblo.edu/ICR/2017

May 2017 Conferences 11th National Clinical Conference on Cannabis Therapeutics Patients Out of Time ~ Cannabis: Protecting Patients and Reducing Harm May 18th - 20th, 2017 | Berkley, CA

http://www.medicalcannabis.com/2017-national-clinical-conference-on-cannabis-therapeutics/

June 2017 Conferences AHNA's 37th Annual Conference- Workshop: Endocannabinoid Connections (June 10th 10:30AM-12Noon) June 5-10th ,2017 | Rancho Mirage, CA www.ahna.org/conference

October 2017 Conferences Cannabis Nurses Magazine 2-Year Anniversary Awards Ceremony | October 7th, 2017 Pre-Course & Event: Cannabis Health & Wellness | October 6th, 2017 October 6-7th, 2017 | Las Vegas, NV Stonefield National: lisa@stonefieldnational.com | www.CannabisNursesMagazine.com If you know of other Conferences available that are based on Cannabis Therapeutics that you wish to be listed in future issues please email us at: editor@cannabisnursesmagazine.com January/February 2017 CANNABISNURSESMAGAZINE.COM

Order your Printed Subscription Today! Inside you'll find:

Informative and Evidence-Based Education with Resources and References - Written by Real Nurses, Doctors, and Scientists.

1-Year Subscription: ___6 issues (1 year) for $36.00 + S.H. 2-Year Subscription: __6 issues (2 years) for $60.00 + S.H. (save $12.00)

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