How Cannabis Helps Treat Breast Cancer By Dr. Veronique Desaulniers
Dr. Christina Sanchez: The Importance of Both THC and CBD in Breast Cancer Healing
In workshops all of over the country as well as with the hundreds of individuals I coach each year on living a healthy breast lifestyle, I always include information on cannabis therapy as an option for those who are considering protocols for healing breast cancer. This is because I rely on evidence-based medicine for all the natural protocols I design. And, hands down, cannabis research over the last twenty-plus years has proven that marijuana contains many cancer-killing properties that can be of benefit for those who have been diagnosed with or are at risk for Estrogen Positive (ER-positive) breast cancer.
Dr. Christina Sanchez of Compultense University in Madrid, Spain was one of the first researchers to specifically focus on breast cancer and cannabis. Her cancer research for over a decade provided deeper insight on how a properly-functioning endocannabinoid system assists in the healthy functioning of every organ system in the body, including the nervous, reproductive and immune systems. Her research during the 1990’s and 2000’s into how both THC and CBD affect breast cancer led to exciting discovering regarding the apoptotic (cancer-killing) effects of cannabinoids.
Her most recent research, however, has proved to be equally as exciting. She and her team at Computense University’s Cannabinoid Signalling Group (a part of CU’s Department of Biochemistry and Microbiology) are currently revealing how newly-discovered cannabinoid receptors, such as CB2, effect anti-tumoral activity in ER-positive breast cancers and other kinds of tumors.
“Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with prognostic value in these tumors,” writes Sanchez and her team in a 2015 report for the Journal of the National Cancer Institute.
More Research on Cannabis and Breast Cancer
Other studies have validated Dr. Sanchez’s findings over the years. A 2011 Harvard University study focused on cannabis’ effect on breast cancer cell programmed death as well as on cellular autophagy, the way in which cells are recycled to create new cellular formation. For cancer cells, autophagy can be a mechanism for tumor suppression or cancer cell survival. According to the Harvard study, CBD in particular influenced methods of communication between “autophagic and apoptotic signaling pathways” which led to tumor reduction and apoptosis.
Other studies have discovered how cannabinoid therapy may affect the genes involved in the spread of breast cancer. Dr. Sean McAllister of California Pacific Medical Center, and his San Francisco-based team are focusing their research on how cannabinoids, in particular CBD, can inhibit human breast cell growth through inhibiting genetic communication, including those cellular signaling pathways that control proteins commonly found in highly-aggressive forms of metastatic breast and brain cancers.
“We find when you treat with [Cannabidiol], you down regulate the expression of this protein, and that inhibits the disease process,” says McAllister.
The Entourage Effect of Cannabis for Breast Cancer
“One of the advantages of cannabinoid-based medicines would be that they target specifically tumor cells,” Dr. Sanchez said in a 2011 video interview. “They don’t have any toxic effect on normal non-tumoral cells. This is an advantage with respect to standard chemotherapy, that targets basically everything.”
This is also the reason why finding the right kinds of all-natural, organic and herbal (not synthetic) cannabinoid preparations are the most effective way to go when considering cannabis for your breast cancer protocol. Part of this journey has to include learning how the different components within cannabis work together for cancer healing.
First, there is the difference between different strains of cannabis: indica, sativa and ruderalis cannabis.
“While all three produce cannabinoids such as THC and CBD, cannabis ruderalis (also known as hemp) does not contain them in a high enough concentration to have a therapeutic effect,” say Drs. Matik Burnett and Amanda Reiman in a recent joint-article for the Drug Policy Alliance.
In addition, each cannabis plant contains over 400 different chemical compounds, including dozens of terpenes, flavonoids, and cannabinoids. While research into the breast cancer-busting effects of specific cannabis strains is still in its infancy, current studies strongly suggest that certain terpenes within the various strains of cannabis may play a role on effectiveness against specific forms of cancer.
The interactions between terpenes and cannabinoids that promote healing is referred to as the “entourage effect.” Some terpenes, for example, have the effect of buffering the psychoactive nature of THC, while others, such as mycene, enhance it. Some terpenes, such as borneol, are able to quickly breach the blood-brain barrier. Others, such as Beta-Caryophyllene (a sesquiterpene also found in black pepper and oregano), has shown to have an effect on inflammation and autoimmune conditions, in part because of its ability to bind directly to the CB2 receptor, an integral part of the endocannabinoid system.
Dr. Ethan Russo, a neurologist who writes extensively on cannabinoid therapy and the endocannabiniod system, states in his 2011 report for the British Journal of Pharmacology that cannabinoid-terpenoid interactions “could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal, and bacterial infections.”
As science– and necessity– uncovers more and more about the healing power of cannabis for cancer, the amount of information out there can sometimes be overwhelming, especially if you are also dealing with the emotional stress of a recent diagnosis. The best way to discover which kinds of cannabinoid therapy is right for you is to work directly with a health professional who has had training in cannabinoid therapy. United Patients Group is a great resource for connecting patients with qualified, trained professionals in states where medical cannabis is legal. Find out what the status of your state is. Then learn all you can about the awesome power of cannabis for your healthy breast journey.
Breast Cancer, Cannabis, and Tamoxifen: Understanding the Dangers of Drug-Drug Interactions
Breast Cancer: Not Just One Disease
Unlike most forms of cancer, “breast cancer” is actually a blanket term rather than a single diagnosis. It covers several distinct types of cancer that are further distinguished by diagnostic laboratory tests. The specific diagnosis drives individual considerations among patients and their medical teams regarding which treatments are most likely to produce the optimal outcomes for each patient.
- Estrogen-receptor positive or negative (ER+ or PR-): Roughly 80% of breast cancer cells tested in labs are positive for estrogen receptors, which means estrogen may support and fuel the cancer’s growth. The remainder are estrogen-receptor negative.
- Progesterone-receptor positive or negative (PR+ or PR-): In addition to receptors for estrogen, tumors may also have receptors for progesterone. About 65% of breast cancers are both ER+/PR+, while 13% are ER+/PR-, 2% are ER-/PR+, and a final 25% are ER-/PR- (receptors for neither estrogen nor progesterone).
- HER2 status: Human epidermal growth factor receptor 2, or HER2, is a gene that plays a role in about 25% of breast cancers. The gene malfunctions, creating too many copies of itself, which ultimately makes HER2-positive breast cancers grow and spread more rapidly than other types of breast cancer.
- Triple-positive: With receptors for both estrogen and progesterone as well as overexpression of the HER2 gene, triple-positive breast cancer has more conventional treatment options than others.
- Triple-negative: These breast cancers do not show receptors for estrogen, progesterone, or HER2 gene overexpression. Because of this lack of receptors, this type of breast cancer is difficult to target with hormones or drugs that target HER2.
Tamoxifen, Hormones, Receptors, and the Immune Response
Tamoxifen is the oldest and most widely used of a class of drugs called Selective Estrogen Receptor Modulators (SERMS). Tamoxifen and other SERMS are commonly prescribed for women with hormone-sensitive breast cancers as one option to attempt to control the growth and spread of the cancer. The intended benefit is to block the estrogen receptors and to interfere with circulating estrogen’s ability to bind and stimulate the tumor cells.
Tamoxifen is a “pro-drug,” which means it is not fully effective until it is metabolized by the liver into its more potent anticancer form through a specific enzyme and metabolic pathway. This metabolic process can be interrupted, inhibited, or even entirely blocked by other substances, both common and uncommon–including large doses of cannabis.
Perhaps the most common food-drug interaction that many people are already familiar with from warning labels and their own physicians is the grapefruit interaction; many pharmaceuticals come with specific warnings not to take them with grapefruit, because grapefruit contains enzymes that inhibit CYP450 metabolism. Tamoxifen is one of these drugs. And cannabinoids, like grapefruit, are known to inhibit CYP450 metabolism.
To date, it appears that THC is mostly metabolized and inhibits the metabolism pathways CYP2C9 and CYP3A4. CBD is reported to be mostly metabolized via and inhibits the pathways CYP2C19 and CYP3A4. CBD appears to inhibit at least CYP3A4 more significantly than THC. But more research is needed to begin to clarify what constitutes a small or large dose. Individuals will also learn that they may metabolize certain medicines and foods differently due to genetic variations affecting metabolism.
“Because grapefruit is a commonly-encountered food that is famous as a CYP450 inhibitor, which should not be used with some medications, I often use it as a surrogate for CBD and THC to check for potential drug interactions,” says Wohlschlagel. ”Due to the historic lack of research on cannabis, we do not have a wealth of research on its potential drug-drug interactions. But when I educate patients, I tell them to check for grapefruit interactions on trustworthy pharmaceutical websites like WebMD. There, they will see that using tamoxifen with grapefruit—and, we must conclude, large doses of cannabinoids as well—could risk reducing the hormone-blocking effects of tamoxifen for breast cancer patients. This could be critical for their outcomes.”
Other drugs metabolized through the same pathways, including popular antidepressants like Paxil, are also on the list of drugs to avoid while taking tamoxifen.
It’s well-known that many forms of cancer respond positively to the anti-proliferative (anti-growth) properties of THC, which binds to cannabinoid receptors in tumors and causes them to stop growing or even to shrink. But a 2015 European study found at least 20% of breast cancer biopsies samples examined did not over-express any CB2 cannabinoid receptors, even in low numbers. There will also likely be various individual tumor mutations that can potentially cause resistance to the effects of THC, as can happen with any therapy. That means the potential benefits of cannabis for treating breast cancer are not as cut-and-dry as oversimplified “natural healing” blogs and headlines sometimes imply. Most patients are using cannabis medicines integrated with conventional therapies.
In fact, in addition to possibly interfering with hormone-suppressing activity of tamoxifen, larger doses of THC can also suppress the body’s T-cell proliferation, which is a part of the immune system that is critical for tumor cell growth suppression. In these cases, the use of high-THC forms of cannabis could theoretically not only not help, but could also make matters worse, allowing the tumor cells to grow more rapidly.
Medical Guidance is Critical
Only a patient’s physician and medical team can offer individual medical advice. If a breast cancer patient feels strongly that cannabis is important to use, those who have been prescribed tamoxifen should be forthright, up-front, and completely honest with her (or his) physicians about using cannabis – especially because the most beneficial amounts of THC and CBD could be quite different depending on the diagnosis.
Small doses of cannabis medicines used are much less likely to cause any significant drug interactions, but some patients are using doses much higher than historically common. Because CBD-rich medicines will not cause as much psychoactivity, people can easily use large doses (75 mg CBD per day or more) without feeling any significant side effects. While large doses may be considered generally safe, the potential for side effects and potential interactions with other therapies is increased at these levels.
Tamoxifen and SERMS
Someone taking tamoxifen or one of the other SERMS needs to understand that there may be some risk of drug-drug interaction, including a possible competition for cannabinoid receptors by the SERMS. This could potentially reduce the effectiveness of the cannabis medicines.
Because large doses of cannabinoids like CBD and THC can inhibit metabolism or processing of substances by the liver, reviewing this potential with your healthcare team is important.
There are alternatives to Tamoxifen which are effective and considered “standard of care” by oncologists. One of the main alternatives is to suppress the ovarian function, including estrogen production, using injectible medications such as Lupron or Zoladex. Again, this is a matter to review and discuss with a comprehensive health care team. Managing the hormonal aspect of most breast cancers can be crucial to treatment.
The Importance of Informed Medical Guidance
Above all, Wohlschlagel is a fierce and outspoken advocate for women and men who are living with and through the constellation of diseases we call “breast cancer.” And while she recognizes that there is a place in the treatment regime for cannabis for many of them, she also wants to emphasize that it is not a panacea, and it is not a cure-all.
“There is not enough evidence-based, scientifically sound information available for patients to do this on their own,” she says. “It’s impossible to fully address the pros, the cons, the potential for benefits and the potential for harm in a blog post or on a Facebook page. There are multiple potential drug interactions that could leave any single patient better or worse off. It is critically important to get a medical team who understands the implications of cannabis and breast cancer on board. I’ve interviewed young women with hormone-positive breast cancer who have reported doing poorly when they tried to use high doses of THC—their disease advanced rapidly, sometimes in a matter of weeks. Some reported that they were also using tamoxifen during that time. Did the tamoxifen interfere with cannabinoid actions? Or did the tamoxifen metabolism get reduced by the large doses of THC they were taking? Since they reported they had been using 100 or more milligrams of THC each day, it is impossible to know for certain. But it certainly raised my awareness of the potential issues that patients may experience.”
“How this is all interacting is a question that will take time to clarify,” she says, “and more research is urgently needed. Then there’s another factor: All tumors can mutate or change when it is treated or spreads, which can change the efficacy of all medications, even when they have been previously helpful. Close monitoring with scans or tumor markers of cancer status is very important, possibly including genomic reassessment of the tumors over time. We are thankfully getting much closer to precision or personalized therapies for many forms of cancer. Unfortunately not all patients and doctors realize how rapidly genomic testing is changing cancer therapy choices, potentially opening up treatment options customized to their unique needs.”
Beyond Tamoxifen: Cannabis and Aromatase Inhibitors
For women (and men) with breast cancer who are not taking tamoxifen—those who are post-menopausal, are using ovarian suppression medications, or who have no ovaries—a physician may prescribe an aromatase inhibitor (Arimidex, Aromasin, or Femara) to help reduce estrogen produced in body tissues other than ovaries. Wohlschlagel says some of these appear to be significantly safer to use with cannabis extracts because they are not metabolized in the same way as tamoxifen, and they do not appear to bind with CB1 and CB2 receptors, leaving those potential targets open for THC to bind to. However several of those (one example is Arimidex) also may be impacted if taken along with strong inhibitors of the CYP3A4 enzyme pathway, such as large doses of CBD and THC. Please speak to your doctor or pharmacist about this.
Testicular Cancer and Marijuana Information: Treat Testicular Cancer With Cannabis
Testicular cancer is a disease in which malignant (cancer) cells form in the tissues of one or both testicles. The testicles are 2 egg-shaped glands located inside the scrotum (a sac of loose skin that lies directly below the penis).
The testicles are the male sex glands and produce testosterone and sperm. Germ cells within the testicles produce immature sperm that travel through a network of tubules and larger tubes into the epididymis where the sperm mature and are stored.
Almost all testicular cancers start in the germ cells. The two main types of testicular germ cell tumors are seminomas and nonseminomas. These 2 types grow and spread differently and are treated differently.
Risk factors for testicular cancer include:
- Having had an undescended testicle
- Having had abnormal development of the testicles
- Having a personal history of testicular cancer
- Having a family history of testicular cancer (especially in a father or brother)
- Being Caucasian
Signs and symptoms of testicular cancer include:
- Swelling or discomfort in the scrotum
- A painless lump or swelling in either testicle
- A change in how the testicle feels
- A dull ache in the lower abdomen or groin
- Pain or discomfort in a testicle or in the scrotum
Uterine Cancer and Marijuana Information: Treat Uterine Cancer With Cannabis
The uterus is a hollow organ in females located in the pelvis, commonly called the womb. The uterus functions to support fetal development until birth. The uterus is shaped like an upside down pear; the top is the fundus, the middle is the corpus, and bottom is the cervix.
Uterine cancer can start in different parts of the uterus. Most uterine cancers start in the endometrium (the inner lining of the uterus). This is called endometrial cancer. Most endometrial cancers are adenocarcinomas (cancers that begin in cells that make mucus and other fluids). Uterine sarcoma is an uncommon form of uterine cancer that forms in the muscle and tissue that support the uterus.
Symptoms of uterine cancer include:
- Abnormal vaginal bleeding, spotting, or discharge
- Pain or difficulty when emptying the bladder
- Pain during sex
- Pain in the pelvic area
The following factors may raise a woman’s risk of developing uterine cancer:
- Age – Uterine cancer most often occurs in women over 50
- Obesity – Fatty tissue produces additional estrogen, a sex hormone which can increase the risk of uterine cancer
- Genetics – Uterine cancers may run in families where colon cancer is hereditary
- Other health conditions – Women may have an increased risk of uterine cancer if they have had endometrial hyperplasia or if they have diabetes.
- Other cancers – Women who have had breast cancer, colon cancer or ovarian cancer may have inherited a genetic mutation (a change) that also causes an increased risk of uterine cancer.
- Tamoxifen – Women taking the drug tamoxifen to prevent or treat breast cancer have an increased risk of developing uterine cancer. However, the benefits of tamoxifen usually outweigh the risk of developing uterine cancer.
- Radiation therapy – Women who have had previous radiation therapy for another cancer in the pelvic area have an increased risk of uterine cancer.
- Estrogen – Longer exposure to estrogen and/or an imbalance of estrogen (women who started having their periods before age 12; women who take hormone replacement therapy after menopause, and women who have never been pregnant)
Glioblastoma Multiforme and Marijuana Information: Treat Brain Cancer With Cannabis
Glioblastoma, also known as glioblastoma Multiforme, GBM or grade IV astrocytoma, is a fast-growing, aggressive type of central nervous system tumor that forms on the supportive tissue of the brain. Glioblastoma is the most common grade IV brain cancer. Glioblastomas may appear in any lobe of the brain, but it develops more commonly in the frontal and temporal lobes. Glioblastoma usually affects adults, and is more common in adults 50 or older.
Symptoms of glioblastoma vary depending on the location of the tumor, but they may include:
- Persistent headaches
- Double or blurred vision
- Nausea and/or vomiting
- Loss of appetite
- Changes in mood or personality and/or changes in ability to think and learn
- Memory loss
- New onset of seizure
- Muscle weakness
- Speech difficulty
Brain cancer does not behave in the same way as other cancers. Tumors may migrate within the brain, but it is very rare for primary brain tumors to spread outside of the brain, or away from the central nervous system (CNS).
Consequently, brain cancer is usually graded rather than staged. Brain cancer grading is much different than staging other cancers in the body. Cancers in the lung, colon and breast are staged based on their location in the body, size, lymph node involvement, and possible spread. Tumors in the brain are graded based on how aggressive the tumor cells appear under a microscope.
Killing Cancer Stem Cells, If You Have Cancer, Pay Attention! By Dr. Veronique Desaulniers
What are Cancer Stem Cells?
Healthy stem cells exist in every organ in your body and are absolutely vital for health and well-being. They are “blank slates” but are also “regenerative powerhouses” that carry within them the potential to develop into many different kinds of cells needed for healthy bodily functions. They contribute to your body’s internal repair mechanisms, especially during the early years of development and they have the ability to divide without limit and to replenish the numbers of cells in a particular area that may be dwindling. Although they can remain a stem cell, they also have the ability to turn into a muscle cell, an organ cell or even a brain cell.
Of course, stem cells can also change into cancer cells under the right conditions; when this happens, then they become deadly. For those with Breast Cancer, according to the principles of cancer stem cell theory “Breast Cancer Stem Cells can be responsible for a relapse even after all ‘observable’ signs of tumor are gone.”
Cancer Stem Cells (CSCs) have the ability to lay dormant until long after treatment has completed and then they can turn into other types of cancer tumor cells, spreading to other parts of the body in the process known as metastasis. BCSCs in particular have been shown to be highly “tumorigenic” (i.e. prone to growing new tumors). What’s more, recent research has shown that traditional chemotherapy treatment may increase the number of BCSCs and other Cancer Stem Cells, thus contributing to a higher rate of tumor growth overall.
What YOU Can Do to Eliminate Cancer Stem Cells
If you are learning about CSCs for the first time, this news may be shocking. Don’t lose hope! Whether you choose to undergo radiation treatment or not, there ARE things you can do to eliminate cancer stem cells. The really good news is that there are natural substances whose specific job it is to destroy cancer cells and cancer stem cells.
Nature never ceases to amaze!
Here are just a few completely natural elements that have been proven to hunt out and destroy Cancer Stem Cells while leaving healthy cells alone:
- Sulforaphane. Sulforaphane is found in cruciferous vegetables and especially in broccoli sprouts. It has been proven by numerous studies to destroy Cancer Stem Cells, especially in the ground-breaking work of Dr. Paul Talalay of John Hopkins University.
- Curcumin. Studies have shown that when curcumin, an anti-inflammatory substance derived from turmeric, is combined with the substance peperine (from black pepper) the duo can eliminate BCSCs
- Ginger. Ginger contains the chemical 6-shogaol, which has been proven specifically to target and kill BCSCs
- Resveratrol.Resveratrol is a Cancer Stem Cell- killing plant compound that is found in the skin of red grapes and other dark berries, especially blueberries. It can also be found in red wine and dark chocolate
- Turkey Tail mushrooms. Mushrooms have long been known to have many immune-boosting and cancer preventative properties. However, a string of studies beginning in the early 2010’s also discovered that Turkey Tail mushrooms from Asia in particular have strong Cancer Stem Cell busting properties, especially for prostate and breast cancers.
If you are concerned about whether you still have Cancer Stem Cells in your system, consider getting a test called the Breast Oncotrail (available through R.G.C.C. Labs in Greece). Then put your reliance on one of the many natural substances that can not only boost and repair your immune system naturally, but also have the ability to keep Cancer Stem Cells and BCSCs forever at bay.
Adrenal Cortical Cancer and Marijuana Information: Treat Adrenal Cortical Cancer With Cannabis
Adrenal cortical carcinoma (ACC) is a rare disease. It is caused by a cancerous growth in the adrenal cortex, which is the outer layer of the adrenal glands. The adrenal glands lie on top of the kidneys. They play an important role in the endocrine system, which is the system that produces and regulates hormones.
Each adrenal gland has two parts. The outer layer of the adrenal gland is the adrenal cortex. The center of the adrenal gland is the adrenal medulla. The adrenal cortex makes important hormones that:
- Balance the water and salt in the body
- Help keep blood pressure normal
- Help control the body’s use of protein, fat, and carbohydrates
- Cause the body to have masculine or feminine characteristics
The adrenal medulla makes hormones that help the body react to stress. Cancer that forms in the adrenal medulla is called pheochromocytoma.
Cancer that forms in the adrenal cortex is called adrenocortical carcinoma. A tumor of the adrenal cortex may be functioning (makes more hormones than normal) or nonfunctioning (does not make more hormones than normal). A functioning adrenocortical tumor makes too much of one of the following hormones: cortisol, aldosterone, testosterone, or estrogen. Too much of any of these hormones can cause problems.
Symptoms of ACC include:
- A lump in the abdomen
- Pain in the abdomen or back
- A feeling of fullness in the abdomen
Prostate Cancer and Marijuana Information: Treat Cancer With Cannabis
The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications
Prostate cancer is a global public health problem, and it is the most common cancer in American men and the second cause for cancer-related death. Experimental evidence shows that prostate tissue possesses cannabinoid receptors and their stimulation results in anti-androgenic effects. To review currently relevant findings related to effects of cannabinoid receptors in prostate cancer. PubMed search utilizing the terms “cannabis,” “cannabinoids,” “prostate cancer,” and “cancer pain management,” giving preference to most recent publications was done. Articles identified were screened for their relevance to the field of prostate cancer and interest to both urologist and pain specialists. Prostate cancer cells possess increased expression of both cannabinoid 1 and 2 receptors, and stimulation of these results in decrease in cell viability, increased apoptosis, and decreased androgen receptor expression and prostate-specific antigen excretion. It would be of interest to conduct clinical studies utilizing cannabinoids for patients with metastatic prostate cancer, taking advantage not only of its beneficial effects on prostate cancer but also of their analgesic properties for bone metastatic cancer pain.
Prostate cancer is an established public health concern in modern society and has been for decades. It is the most common cancer in men (asides from non-melanoma skin cancer) and the second most common cause of cancer death in the United States. Even with widespread screening with prostate-specific antigen (PSA), still 5% of cases present with metastatic lesions at the time of diagnosis. Because of all this, there is a fundamental necessity to search for and find new and novel treatments to this common pathology. Cannabis and cannabinoids have often been an issue of much polemics in the realm of science, but since the discovery of cannabinoid receptors in rat brain in the late 1980s, there has been a growing interest in the research of these compounds and our knowledge continues to expand. There has been experimental evidence that cannabinoids possess anti-androgenic proprieties; the purpose of this review is to describe in detail the effects, characteristics, and possible role of cannabis and cannabinoids in the subject of prostate cancer.
MATERIALS AND METHODS
A PubMed search was conducted for manuscripts published regardless of publication date, which contained the terms “cannabis,” “cannabinoids,” “prostate cancer,” and “cancer pain management,” giving preference to most recent publications. Articles identified were screened for their relevance to the field of prostate cancer and likely interest to both urologist and pain specialists. This review article focuses on the effects of cannabinoids in the realm of prostate cancer pathophysiology and their potential uses.
Overview: Prostate cancer
Prostate cancer is the most common cancer in American men except for non-melanoma skin cancer. In the United States, an estimated 217,730 cases will be diagnosed in 2010 and 32,050 deaths will occur. Its frequency has increased in part due to the widespread availability of serum PSA testing. Its incidence peaked in 1992, declined between 1992 and 1995, and has been rising about 1% annually since then[1,4] until 2000-2006, since then incidence rates have declined by 2.4% per year, which may reflect recent stabilization of PSA testing.[5–7] Widespread PSA use has led to an increasing proportion of prostate cancer cases that are localized at diagnosis, with fewer patients presenting with metastatic disease. As an example, between 1984 and 1991, 30–40% of men presented with advanced disease, and currently only 5% have distant metastases at the time of diagnosis. Prostate cancer remains the second most common cause of cancer death in American men.
Despite the fact that a higher percentage of men have localized disease at presentation, metastatic prostate cancer remains an important clinical problem, both in terms of the number of affected men and its impact on their quality of life. Hematogenous spread of prostate cancer cells is a common event. For these malignant cells, tumor growth preferentially occurs in bones of the axial skeleton. The most common site of metastasis is bone and frequently is symptomatic, causing pain, debility, and functional impairment. The presence of pain in men with advanced prostate cancer is an immediate indication for aggressive management with analgesics, while adequate treatments that address directly the cause of the pain are pursued.
Numerous treatment options have been established to treat bone metastatic prostate cancer; some focus on treating the underlying pathophysiology, while others focus on pain management and palliative care. Examples of the former are androgen deprivation therapy (ADT), being the initial approach in most cases, it alleviates pain from bone metastases to 80–90%. Second-line hormonal therapy with systemic chemotherapy with docetaxel and mitoxantrone,[11,12] may be beneficial when the initial ADT regimen is no longer effective. More local modalities also considered in today’s medical world are focal external beam radiation therapy, an excellent treatment choice for men with castrate-resistant prostate cancer and bone pain that is limited to one or a few sites, bone-targeted radioisotopes 89-strontium (89Sr) and 153-samarium (153Sm) for multiple blastic bone lesions, and radiofrequency ablation.
Role of cannabinoids in male physiology
Cannabis is a bushy plant with palmate leaves and clusters of small green flowers, and it grows wild in regions of tropical weather and can attain up to 3 m height. The genus Cannabis is complemented by sativa which translates to useful. Cannabis has indeed been used throughout history for a variety of purposes, including the production of fiber for paper and textile manufacture. However, its current popularity lies in its use as a recreational drug with psychoactive properties. The plant contains many chemical compounds that have different pharmacological properties, varying in quantity and quality depending on the strain, culture, and storage conditions.
In 1964, Mechoulam and colleagues found that delta-9-tetrahydrocannabinol (THC) was the major psychoactive ingredient of cannabis. However, the endocannabinoid signaling system has only been the focus of medical research and considered a potential therapeutic target in recent times.[15–17] During the late 1980s Howlett and colleagues identified and characterized a receptor in rat brain that met criteria for a high-affinity, stereoselective, pharmacologically distinct cannabinoid receptor, by means of radiolabelled agonist ligand binding and functional assays for G-protein coupled receptors.
In the United States, cannabis has been illegal since 1937, and currently 14 states (Alaska, California, Colorado, Hawaii, Maine, Michigan, Montana, Nevada, New Jersey, New Mexico, Oregon, Rhode Island, Vermont, and Washington) and DC have enacted laws that legalize medical marijuana, requiring it to be prescribed by physicians and being especially used to relieve AIDS patients treatment side effects. The frequently held view of cannabis and its related products as drugs of abuse have slowed progress in the development of studies designed to take advantage of the properties of cannabinoid derivatives for therapeutic purposes.
The antagonizing effect of cannabinoids in the male reproductive system and physiology can be dated to 1974 where experimental models in male rats showed depression of spermatogenesis and decrease in circulating testosterone levels. Chakravarty and colleagues[23,24] in 1980-1981 demonstrated how administration of cannabis reduced levels of fructose and citric acid, and decreased glucuronidase, glycosidase, and acid phosphatase levels in accessory reproductive organs of male rats, most of these which are regulated by circulating levels of testosterone, suggesting at the time a possible anti-androgenic effect of cannabis.
Current basic science research
In recent years, cannabinoids and their derivatives have drawn renewed attention due to the discovery of diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects, and tumor regression.[25–30] Focusing on prostate cancer, in 2005, Sarfaraz and colleagues showed that expression of both CB1 and CB2 receptors was significantly higher in cultured prostate cancer cells LNCaP, DUI45, PC3, CWR22Rr1, and CAHPV-10 when compared with normal prostate cells PZ-HPV-7 and PrEC. Data also show that treatment of LNCaP prostate cancer cells with cannabinoid CB1/CB2 agonist WIN-55,212-2 results in a significant dose- and time-dependent decrease in cell viability and increased apoptosis of the former at 24 and 48 hours, with no significant change in apoptosis of the normal prostate epithelial cells at similar doses. When the same cells were pretreated with cannabinoid receptor antagonists SR141716 (CB1 antagonist) or SR144528 (CB2 antagonist), the coadministration of WIN-55,212-2 had no effect on cell viability, exhibiting a significant protective effect. These data suggest that both CB1 and CB2 receptors may be involved in WIN-55,212-2-mediated growth inhibition and apoptosis.
Androgens are involved in the maintenance and progression of prostate cancer, where the androgen receptor is assumed to be the essential mediator for androgen action.[31,32] Sarfaraz’ study also showed that stimulation of cannabinoid receptors resulted in a marked decrease in androgen receptor protein expression and a dose-dependent decrease in PSA expression and secreted PSA (secreted levels of PSA decreased by 30%, 53%, and 62 % at 5.0, 7.5, and 10 Amol/L, respectively) at 24 hours. PSA is considered as the most sensitive biomarker and screening tool for prostate cancer to date; its regulation is androgen-dependent.
On a future study, Sarfaraz and colleagues revealed the molecular bases for increased apoptosis and cell inhibition in prostate cancer cells treated with cannabinoid agonists, showing that treatment with WIN-55,212-2 resulted in arrest of the cells in the G0/G1 phase of the cell cycle; induction of p53 and p27/KIP1 genes; down-regulation of cyclins D1, D2, E; decrease in the expression of cdk-2, -4, and -6; and decrease in the protein expression of DP1and DP2. Curiously enough it was determined that high cannabinoid CB1 receptor immunoreactivity is associated with greater disease severity and poorer outcome in prostate cancer patients. In this study, 42% of the high CB1 receptor immunoreactivity group on prostate biopsy presented with Gleason scores of 8–10 when compared with 12% in the low CB1 receptor immunoreactivity. The incidence of metastases at diagnosis was also higher in the high CB1 receptor immunoreactivity (17%) than in the low group (5%). Patients with high CB1 receptor immunoreactivity showed a significantly worse survival rate than those with low CB1 receptor immunoreactivity (hazard ratio 2.51, with 95% confidence limits of 1.43–4.43; P < 0.05). A possible explanation for these results that is in synch with the cell line data is that the expression of CB1 receptors is regulated by the local endocannabinoid release. The author’s conclusion in this scenario was that a low endocannabinoid tone would allow for an increased rate of proliferation, resulting in a compensatory increase in surface expression of CB1 receptors.
Cannabinoids in cancer pain management
Cannabinoid CB1 receptors are found mainly in the central nervous system and, in less abundance, in certain peripheral tissues. At the peripheral level, they are localized in the adrenal gland, adipose tissue, heart, liver, lung, prostate, uterus, ovary, testis, bone marrow, thymus, tonsils, and presynaptic nerve terminals.[37–42] More significantly for the purposes of the present review, they are found at central and peripheral levels of the pain pathways.[39–47] The distribution of cannabinoid receptors provides an anatomical explanation for the analgesic effects of the cannabinoids. Activation of presynaptic CB1 receptors in different brain regions or on primary afferents inhibits the release of neurotransmitters by decreasing calcium conductance and by increasing the conductance of potassium. Neurophysiological studies by Walker’s laboratory first documented that cannabinoids suppress nociceptive processing.[48–50] Cannabinoids, administered systemically, suppress activity of nociceptive neurons in the spinal dorsal horn and ventralposterior lateral nucleus of the thalamus, without altering the activity of purely non-nociceptive neurons. Stimulation-produced analgesia was blocked by the CB1 antagonist SR141716A, demonstrating mediation by the CB1 receptor.
Delta-9-THC is the substance with the greatest psychoactive potency of the natural cannabinoids and exhibits the greatest analgesic activity. Cannabidiol (CBD), another major constituent of the Cannabis sativa plant, has the same therapeutic effects of THC (analgesic, anti-inflammatory, and others), but with a different pharmacologic profile. Studies with CBD derivatives developed to inhibit peripheral pain responses and inflammation after binding to cannabinoid receptors have been described. Interestingly, some of these CBD derivatives did not have central nervous system effects, but maintained their antinociceptive and anti-inflammatory properties. This means that centrally inactive synthetic CBD analogues may be candidates for the development of analgesic and anti-inflammatory drugs for peripheral conditions without major central nervous system alterations of the sensorium.
In animal models of cancer bone pain, synthetic cannabinoids reduced hyperalgesia by a CB1 receptor-mediated effect and possibly at the peripheral CB2 receptor. In some models, cannabinoids were superiorly effective in cancer pain when compared with other pain types.[54–58]
Clinical trials have shown that nonselective cannabinoid receptor agonists are relatively safe and therapeutically efficacious, however, inducing also psychotropic side effects.
Cannabinoid efficacy has also been studied clinically in cancer pain. Initial studies quantified the modest efficacy of oral 20 mg D9-THC equivalent to 120 mg codeine with some sedation, dizziness, and confusion.[54,60,61] Recently in an observational study of patients with advanced cancer pain, nabilone reduced pain scores, total opioid requirements, and nausea. Nabilone did not significantly increase adverse effects compared with the control group, and this fact could be attributed to the concurrent decrease in opioid dose.
Uncontrolled pain can cause unnecessary suffering, decreased ability to cope with illness, interference with daily activities and extended hospital admissions, and decreasing overall quality of life.[63,64] The usual approach to cancer pain management differs from physician to physician, but a well-known guideline is described in the World Health Organization’s analgesic ladder:[65,66]
Step 1 of the ladder is for patients with mild to moderate cancer-related pain. These should first be treated with acetaminophen or a nonsteroidal antiinflammatory agent (NSAID), possibly combined with an adjuvant drug that provides additional analgesia (i.e., an analgesic antidepressant drug for neuropathic pain), treats a side effect, or manages a coexisting symptom.
Step 2 describes patients with moderate or severe pain, including those who do not achieve adequate relief after a trial of an NSAID alone; these should be treated with an opioid.
The analgesic ladder promoted the doctrine of using an opioid of inferior analgesic properties (i.e., codeine as the prototype) to treat pain of moderate intensity on step 2 and strong opiates as morphine or hydromorphone for severe pain on step 3.
On both steps 2 and 3, combination therapy that includes an NSAID or other drugs to enhance analgesia or treat side effects is advocated.
The combination of two antinociceptive drugs acting through different specific receptor systems provides major benefits. When synergistic substances are given in combination, the required dose of each agent can be reduced to less than would be explained by mere addition of individual effects. The clinical benefit of this property is fundamental in analgesic treatments because effective pain relief can be achieved with minor, fewer, or no side effects.
Chronic pain is a difficult subject to approach both for the patient and the treating physician and, not uncommonly, leads to chronic opiate consumption and dependence. Physician and the patients both are left with less and less options, and eventually to resort to alternative modes of therapy. Cannabis has been documented to be one of such measures.
As with any therapeutic modality, adverse effects must be taken into account. A number of patients will suffer from these, although most of them will be present within the first days of treatment and attenuate as they adjust to the drug. Some effects described with cannabis use are short-term unsteadiness, dizziness, difficulty concentrating, drowsiness, dryness of the mouth, and/or headache. Chronic cannabis use does not produce serious cognitive disorders, as occurs with other substances such as alcohol, but it can aggravate preexisting mental disease. Therefore, treatment with cannabinoid receptor agonist with central actions may be contraindicated, in individuals predisposed to or with current psychiatric disorders. No human deaths associated to cannabis use have been reported.
Prostate cancer is a grave public health problem worldwide. Despite the fact that most cases currently present with localized disease at the time of diagnosis, about 5% of men still present with metastatic disease. The most common site of spread is bone, and these lesions are frequently symptomatic, causing pain, debility, and functional impairment. Many of these men do not have curative treatment options, and this remains a crucial clinical problem, both in terms of the number of men affected and its impact on their quality of life. For these reasons, it is fundamental to invest time and intellectual resources into finding new and novel targets for the treatment of prostate cancer.
It seems that the studies of Sarfaraz and colleagues lead to the direction that cannabinoids should be considered as agents for the management of prostate cancer, pending support from in vivo experiments. This would not only make sense from an anti-androgenic point of view but also for men with bone metastatic prostate cancer, perhaps from a pain management or palliative point of view. Among the patients suffering with chronic pain and receiving opioids, one in five abuse prescription controlled substances,[69,70] and it is not difficult to see that opioid dependence and abuse is becoming a public health problem. Different methods of managing pain should be addressed to avoid these scenarios.
The presence of pain in men with advanced prostate cancer is an immediate indication for aggressive management with analgesics, while adequate treatments that address directly the cause of the pain are pursued. Cannabinoids possess attributes that have impact in both cancer pain and prostate cancer pathophysiology. These compounds harbor analgesic properties that aid bone cancer pain, reduce opioid consumption, side effects, and dependence, as well as exhibiting anti-androgenic effects on experimental prostate cancer cells.
Cannabis sativa and its main active component delta-9-THC have long been used for numerous purposes throughout history including medicinal, textile, and recreational. Since its legal banning in the United States in 1937, it has become an issue of taboo and controversy, frowned upon for its recreational uses and psychotropic effects. Nonetheless, the endocannabinoid signaling system has recently been the focus of medical research and considered a potential therapeutic target[15–17] since the late 1980s when Howlett and colleagues identified and characterized the distinct cannabinoid receptor in rat brain. The antagonizing effect of cannabinoids in the male reproductive system and physiology can be dated to 1974 where experimental models in male rats showed depression of spermatogenesis and decrease in circulating testosterone levels. In 2005, Sarfaraz and colleagues showed increased expression of both CB1 and CB2 receptors in cultured prostate cancer cells when compared with normal prostate cells, treatment of prostate cancer cells with cannabinoid CB1/CB2 agonist WIN-55,212-2 results in a dose and time dependent decrease in cell viability ,and increased apoptosis along with decrease in androgen receptor protein expression, PSA expression, and secreted PSA, suggesting that cannabinoids should be considered as agents for the management of prostate cancer. If the hypothesis is supported by in vivo experiments. It is our conclusion that it would be of interest to conduct clinical trials involving medicinal cannabis or other cannabinoid agonists, comparing clinical markers such as PSA with controls, especially in men with bone metastatic prostate cancer, whom would not only benefit from the possible anti-androgenic effects of cannabinoids but also from analgesia of bone pain, improving quality of life, while reducing narcotic consumption and preventing opioid dependence.
Prostate cancer is cancer that occurs in a man’s prostate — a small walnut-shaped gland that produces the seminal fluid that nourishes and transports sperm.
Prostate cancer is one of the most common types of cancer in men. Prostate cancer usually grows slowly and initially remains confined to the prostate gland, where it may not cause serious harm. While some types of prostate cancer grow slowly and may need minimal or no treatment, other types are aggressive and can spread quickly.
The most important factor that determines whether a prostate cancer is “aggressive” or not is the degree to which the prostate cancer cells are abnormal. Extremely abnormal prostate cancer cells behave much more aggressively than near-normal cells.
The prostate cancer grade, often quantified using the Gleason scoring system, is a measure of just how abnormal the prostate cancer cells are. The more abnormal the cells, the higher the grade, and, generally, the more aggressive the cancer.
Cancers can also be more aggressive in men who have other health problems or weakened immune systems. In a sense, the body is not strong enough to fully block the growth of the aggressive cancer.
Prostate cancer may cause no signs or symptoms in its early stages. Prostate cancer that is more advanced may cause signs and symptoms such as:
- Trouble urinating
- Decreased force in the stream of urine
- Blood in the semen
- Discomfort in the pelvic area
- Bone pain
- Erectile dysfunction