Marijuana and Cancer
Marijuana is the name given to the dried buds and leaves of varieties of the Cannabis sativa plant, which can grow wild in warm and tropical climates throughout the world and be cultivated commercially. It goes by many names, including pot, grass, cannabis, weed, hemp, hash, marihuana, ganja, and dozens of others.
Marijuana has been used in herbal remedies for centuries. Scientists have identified many biologically active components in marijuana. These are called cannabinoids. The two best studied components are the chemicals delta-9-tetrahydrocannabinol (often referred to as THC), and cannabidiol (CBD). Other cannabinoids are being studied.
At this time, the US Drug Enforcement Administration (DEA) lists marijuana and its cannabinoids as Schedule I controlled substances. This means that they cannot legally be prescribed, possessed, or sold under federal law. Whole or crude marijuana (including marijuana oil or hemp oil) is not approved by the US Food and Drug Administration (FDA) for any medical use. But the use of marijuana to treat some medical conditions is legal under state laws in many states.
Dronabinol, a pharmaceutical form of THC, and a man-made cannabinoid drug called nabilone are approved by the FDA to treat some conditions.
Types of marijuana compounds
Different compounds in marijuana have different actions in the human body. For example, delta-9-tetrahydrocannabinol (THC) seems to cause the “high” reported by marijuana users, and also can help relieve pain and nausea, reduce inflammation, and can act as an antioxidant. Cannabidiol (CBD) can help treat seizures, can reduce anxiety and paranoia, and can counteract the “high” caused by THC.
Different cultivars (strains or types) and even different crops of marijuana plants can have varying amounts of these and other active compounds. This means that marijuana can have different effects based on the strain used.
The effects of marijuana also vary depending on how marijuana compounds enter the body. The most common ways to use marijuana are in food (edible marijuana) and by smoking or vaping it (inhaled marijuana):
- Edible marijuana: When taken by mouth, such as when it’s used in cooking oils, drinks (beer, tea, vodka, soda), baked goods (biscuits, brownies, cookies), and candy, the THC is absorbed poorly and can take hours to be absorbed. Once it’s absorbed, it’s processed by the liver, which produces a second psychoactive compound (a substance that acts on the brain and changes mood or consciousness) that affects the brain differently than THC. It’s important to know that the amount of THC in foods that have had marijuana added to them is often unknown and getting too much THC might cause symptoms of overdose.
- Inhaled marijuana: When marijuana is smoked or vaporized, THC enters the bloodstream and goes to the brain quickly. The second psychoactive compound is produced in small amounts, and so has less effect. The effects of inhaled marijuana fade faster than marijuana taken by mouth.
How can marijuana affect symptoms of cancer?
A number of small studies of smoked marijuana found that it can be helpful in treating nausea and vomiting from cancer chemotherapy.
A few studies have found that inhaled (smoked or vaporized) marijuana can be helpful treatment of neuropathic pain (pain caused by damaged nerves).
Smoked marijuana has also helped improve food intake in HIV patients in studies.
There are no studies in people of the effects of marijuana oil or hemp oil.
Studies have long shown that people who took marijuana extracts in clinical trials tended to need less pain medicine.
More recently, scientists reported that THC and other cannabinoids such as CBD slow growth and/or cause death in certain types of cancer cells growing in lab dishes. Some animal studies also suggest certain cannabinoids may slow growth and reduce spread of some forms of cancer.
There have been some early clinical trials of cannabinoids in treating cancer in humans and more studies are planned. While the studies so far have shown that cannabinoids can be safe in treating cancer, they do not show that they help control or cure the disease.
Relying on marijuana alone as treatment while avoiding or delaying conventional medical care for cancer may have serious health consequences.
Possible harmful effects of marijuana
Marijuana can also pose some harms to users. While the most common effect of marijuana is a feeling of euphoria (“high”), it also can lower the user’s control over movement, cause disorientation, and sometimes cause unpleasant thoughts or feelings of anxiety and paranoia.
Smoked marijuana delivers THC and other cannabinoids to the body, but it also delivers harmful substances to users and those close by, including many of the same substances found in tobacco smoke.
Because marijuana plants come in different strains with different levels of active compounds, it can make each user’s experience very hard to predict. The effects can also differ based on how deeply and for how long the user inhales. Likewise, the effects of ingesting marijuana orally can vary between people. Also, some chronic users can develop an unhealthy dependence on marijuana.
There are 2 chemically pure drugs based on marijuana compounds that have been approved in the US for medical use.
- Dronabinol (Marinol®) is a gelatin capsule containing delta-9-tetrahydrocannabinol (THC) that’s approved by the US Food and Drug Administration (FDA) to treat nausea and vomiting caused by cancer chemotherapy as well as weight loss and poor appetite in patients with AIDS.
- Nabilone (Cesamet®) is a synthetic cannabinoid that acts much like THC. It can be taken by mouth to treat nausea and vomiting caused by cancer chemotherapy when other drugs have not worked.
Nabiximols is a cannabinoid drug still under study in the US. It’s a mouth spray made up of a whole-plant extract with THC and cannabidiol (CBD) in an almost one to one mix. It’s available in Canada and parts of Europe to treat pain linked to cancer, as well as muscle spasms and pain from multiple sclerosis (MS). It’s not approved in the US at this time, but it’s being tested in clinical trials to see if it can help a number of conditions.
How can cannabinoid drugs affect symptoms of cancer?
Based on a number of studies, dronabinol can be helpful for reducing nausea and vomiting linked to chemotherapy.
Dronabinol has also been found to help improve food intake and prevent weight loss in patients with HIV. In studies of cancer patients, though, it wasn’t better than placebo or another drug (megestrol acetate).
Nabiximols has shown promise for helping people with cancer pain that’s unrelieved by strong pain medicines, but it hasn’t been found to be helpful in every study done. Research is still being done on this drug.
Side effects of cannabinoid drugs
Like many other drugs, the prescription cannabinoids, dronabinol and nabilone, can cause side effects and complications.
Some people have trouble with increased heart rate, decreased blood pressure (especially when standing up), dizziness or lightheadedness, and fainting. These drugs can cause drowsiness as well as mood changes or a feeling of being “high” that some people find uncomfortable. They can also worsen depression, mania, or other mental illness. Some patients taking nabilone in studies reported hallucinations. The drugs may increase some effects of sedatives, sleeping pills, or alcohol, such as sleepiness and poor coordination. Patients have also reported problems with dry mouth and trouble with recent memory.
Older patients may have more problems with side effects and are usually started on lower doses.
People who have had emotional illnesses, paranoia, or hallucinations may find their symptoms are worse when taking cannabinoid drugs.
Talk to your doctor about what you should expect when taking one of these drugs. It’s a good idea to have someone with you when you first start taking one of these drugs and after any dose changes.
What does the American Cancer Society say about the use of marijuana in people with cancer?
The American Cancer Society supports the need for more scientific research on cannabinoids for cancer patients, and recognizes the need for better and more effective therapies that can overcome the often debilitating side effects of cancer and its treatment. The Society also believes that the classification of marijuana as a Schedule I controlled substance by the US Drug Enforcement Administration imposes numerous conditions on researchers and deters scientific study of cannabinoids. Federal officials should examine options consistent with federal law for enabling more scientific study on marijuana.
Medical decisions about pain and symptom management should be made between the patient and their doctor, balancing evidence of benefit and harm to the patient, the patient’s preferences and values, and any laws and regulations that may apply.
The American Cancer Society Cancer Action Network (ACS CAN), the Society’s advocacy affiliate, has not taken a position on legalization of marijuana for medical purposes because of the need for more scientific research on marijuana’s potential benefits and harms. However, ACS CAN opposes the smoking or vaping of marijuana and other cannabinoids in public places because the carcinogens in marijuana smoke pose numerous health hazards to the patient and others in the patient’s presence.
The Highs and Lows of Cannabis in Cancer Treatment and Bone Marrow Transplantation
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In the last decade, we have observed an increased public and scientific interest in the clinical applications of medical cannabis. Currently, the application of cannabinoids in cancer patients is mainly due to their analgesic and anti-emetic effects. The direct effects of phyto-cannabinoids on cancer cells are under intensive research, and the data remain somewhat inconsistent. Although anti-proliferative properties were observed in vitro, conclusive data from animal models and clinical trials are lacking. Since immunotherapy of malignant diseases and bone marrow transplantation are integral approaches in hemato-oncology, the immuno-modulatory characteristic of cannabinoids is a fundamental aspect for consideration. The effect of cannabinoids on the immune system is presently under investigation, and some evidence for its immuno-regulatory properties has been shown. In addition, the interaction of cannabinoids and classical cytotoxic agents is a subject for further investigation. Here we discuss the current knowledge of cannabinoid-based treatments in preclinical models and the limited data in oncological patients. Particularly, we address the possible contradiction between the direct anti-tumor and the immune-modulatory effects of cannabinoids. Better understanding of the mechanism of cannabinoids influence is essential to design therapies that will allow cannabinoids to be incorporated into the clinic.
Keywords: Bone marrow transplantation, cancer, cannabidiol, cannabinoid receptor 2, cannabinoids, cannabis, endocannabinoid, immunotherapy, tumor, Δ9-tetrahydrocannabinol
CANNABIS AND CANCER
Cancer is one of the most prevalent and devastating diseases in the modern world. Its treatments are often highly toxic to healthy tissues, causing severe side effects. In the course of treatment, both curative and palliative care will be administered either exclusively or in combination. As a result of the disease and its curative treatments, patients experience nausea, vomiting, loss of appetite, and pain. These symptoms greatly reduce their quality of life, and first-line palliative interventions are often insufficient for symptom control.
Cannabis and cannabinoids are known for their analgesic and anti-emetic effects, and therefore their application has increased for chemotherapy-induced nausea, vomiting, and chronic pain. 1 Whether cannabinoids have an anti-cancer affect is yet to be determined. Recent studies suggested that some cannabinoid-based treatments might have anti-tumor properties. 2 – 5 Cannabinoids were found to modulate key cell signaling pathways involved in the control of cancer cell proliferation and survival. 6 – 8 However, most of these studies utilized in vitro methods, a few were done in immune-competent animal models, and the data from human patients are anecdotal. In addition, the heterogeneity of endocannabinoids and their receptors in different tumor types raises the possibility that specific cannabinoid compositions should be used to treat differing cancer subtypes. 3 , 9 , 10
CANNABIS AND IMMUNITY IN CANCER PATIENTS
The tumor microenvironment is a complex ecosystem, comprising blood vessels, immune cells, fibroblasts, extracellular matrix, cytokines, hormones, and other factors. The different elements of the tumor microenvironment contribute to cancer progression. In particular, it is now evident that the immune system plays a key role in the development and progression of cancer. 11 – 13 Immune cells possess the ability to eradicate cancer. However, in cancer patients the anti-tumor immune response is insufficient. In recent years, immunotherapy has revolutionized cancer treatment, restoring tumor-induced immune deficiency in the tumor microenvironment and modulating immune responses against cancers. 14 Allogeneic hematopoietic stem cell transplantation (HSCT), which is usually performed for patients with hematologic malignancies, is another treatment that aims to induce anti-tumor immunity by targeting minor histocompatibility antigens on residual cancer cells. Any treatment with immune-suppressive properties may reduce the efficacy of such therapies.
The immune-regulatory properties of cannabis and cannabinoid-based treatments were demonstrated in various preclinical and clinical studies. 15 – 17 It is therefore important to investigate the effects of cannabinoid-based treatments on the immunity of cancer patients and on the efficacy of immune-related therapies. With a greater understanding of cannabinoid-based treatment effects on the immune system we will be able to appropriately apply them to treatment of cancer patients in combination with existing therapies. Unfortunately, the basic and medical research dedicated to this subject is currently lacking.
McKallip et al. demonstrated, in a murine model of breast cancer, that the phyto-cannabinoid Δ9-tetrahydrocannabinol (THC) promotes growth of cancer cells and metastasis by suppression of the anti-tumor immune response. 18 One group demonstrated enhanced tumor growth in THC-treated immune-competent mice but not in immune-incompetent mice in models of lung cancer, 19 while another group showed inhibition of tumor growth by synthetic cannabinoid receptor agonists in both immune-competent mice and immune-incompetent mice, in a model of melanoma xenograft. 20 In an ex vivo experiment, Zgair et al. showed that both phytocannabinoids cannabidiol (CBD) and THC have anti-proliferative effects on peripheral blood mononuclear cells (PBMC) isolated from patients on chemotherapy regimens to treat non-seminomatous germ cell tumors, which were comparable to the effect on PBMCs from healthy volunteers. 16
Only one study has investigated the interaction between phyto-cannabinoids and immunotherapy with checkpoint inhibitors. In this retrospective, observational study in kidney cancer and melanoma patients, Taha et al. demonstrated an inverse relationship between cannabis use and the response to treatment with nivolumab, without affecting progression-free survival or overall survival and without relation to specific phyto-cannabinoid composition. 21
CANNABIS AND IMMUNITY IN HEMATOPOIETIC STEM CELL TRANSPLANTATION
In allogeneic HSCT the propensity of the grafted immune cells to eliminate residual tumor cells is also responsible for rejection of host tissues and the development of graft versus host disease (GVHD). 22 In addition, slow, impaired, or dysregulated reconstitution of donor-derived immune cell populations, together with GVHD and other post-transplant complications, causes susceptibility to both common and rare infections. The early post-engraftment period is characterized by a progressive recovery of cell-mediated immunity; however, full immune reconstitution may take years. 23
In our recently published research, 17 we compared the consequences of treatment with THC and CBD in vitro and in murine bone marrow transplantation (BMT) models. Since it has been suggested that the combination of cannabinoids with other active molecules in the plant may achieve better clinical results than pure cannabinoids (known as the entourage effect), 24 we also examined the differences between the effects of the pure cannabinoids and high THC/high CBD cannabis extracts. Cannabis extracts with a high content (20%–30%) of CBD or THC were named CBD botanical drug substance (BDS) or THC BDS, respectively.
To investigate the effect of THC, CBD, and cannabis extracts on hematopoiesis after BMT in vivo, we utilized a syngeneic transplantation model ( Figure 1A ). Mice underwent lethal whole-body irradiation and were reconstituted with donor bone marrow cells. The cannabinoid treatments were administered intraperitoneally (IP) from the day of transplantation, every other day, for 2 weeks. Once a week, blood was collected for complete blood counts. Surprisingly, all treatments—and especially THC—inhibited lymphocyte reconstitution after transplantation ( Figure 1B ). Only the high-THC extract improved platelet rehabilitation ( Figure 1C ). Indeed, using knockout mice as donors, we have demonstrated that the cannabinoid receptor 2 (CB2), known to be activated by THC, has an inhibitory effect on post-transplant recovery of blood lymphocytes ( Figure 2 ).
Cannabis/Cannabinoids Administration to Syngeneic Bone Marrow Transplantation Model.
A: Recipient C57BL/6 mice (R) received lethal whole-body irradiation and were reconstituted with 8×10 6 donor C57BL/6 (D) bone marrow cells. Cannabis/cannabinoids were administered IP every other day, for 2 weeks from the day of transplantation. Blood samples for complete blood counts were obtained once a week. B: Lymphocyte counts (day 21 after transplantation) in pure cannabinoid-treated groups (left) and BDS-treated groups (right) are presented. C: Platelet counts in pure cannabinoid-treated groups (left) and BDS-treated groups (right), day 14 after transplantation. * PPP
BDS, botanical drug substance; BMT, bone marrow transplantation; IP, intraperitoneally; THC, Δ9-tetrahydrocannabinol.