WHAT IF: CANNABIS CURED CANCER? - DR. ROB SILVER

This article was written for Carnivora™ by Dr. Robert J. Silver DVM, MS
Chief Medical Officer, RxVitamins

A 2500 year old mummy was unearthed in Siberia in 1993. Known as the "Siberian Ice Maiden", her burial chamber contained, among other things, a pouch of cannabis. MRI imaging revealed that the princess had a primary tumor in her right breast with enlarged lymph nodes and metastatic disease. It has been speculated that the cannabis was used to manage her pain and other symptoms, or even had been used as a treatment for her breast cancer.¹⁸

What if cannabis did cure cancer? Cannabis has had the popular "reputation" that it can cause cancer to go into long term remission. and that claim is repeated frequently on the internet. You have on the internet the phenomenon of "Rick Simpson Oil" (RSO), in which Mr. Simpson has cured his own cancer taking a concentrated oil extract he made himself from the cannabis plant. This recipe is available on the internet and there are claims from a number of people who had cancer who tried this approach and reportedly cured themselves.

What are the facts? Are there any clinical trials using cannabis or its derivatives in cancer patients, and what were those trials' outcomes? Are there any trials in veterinary species, other than laboratory animals? This lecture will sort the fact from the fallacious, and present the science that supports the value of cannabis for cancer patients, from a cancer therapy standpoint or from palliation of the adverse side-effects associated with cancer treatment and with cancer itself.

Since the mid-1970s, researchers have been studying the effects that both endogenous and exogenous cannabinoids have on cancer, in vitro, and in vivo. With the on-going legalization of medical cannabis, state by state in over 50% of the US, this topic has now become open to increased investigation. The cannabis plant, the source of plant-based cannabinoids, has been illegal for 70+years in the United States and most of the world.

The two plant-based cannabinoids, cannabidiol (CBD) and Δ9-Tetrahydrocannabinol (THC) are the cannabis plant compounds at the center of these research efforts. Another factor that has been an impediment to veterinary research, specifically, is the lack of state medical cannabis legislation that would allow veterinarians to work with medical cannabis with their patients. This legislation would give veterinarians the same privileges that human physicians have with regard to recommending medical cannabis treatments to their patients.

The Endocannabinoid System And Cancer

The endocannabinoid system (ECS) is a recently discovered signaling system made up of: 1) Endocannabinoid receptors, which are G-protein coupled receptors distributed widely in the central nervous system and immune systems, as well as other bodily systems; 2) Intrinsic lipid ligands, the endocannabinoids AEA (N-arachidonoylethanolamide or "anandamide") and 2-AG (2-arachidonoylglycerol); and 3) the transporters and biosynthetic and degradative enzymes. The endogenous ligands will also bind to other receptors such as the TPRV1 (vanilloid or capsaicin) receptor, the GPR55 "orphan" receptor, the peroxisome proliferator-activated receptor (PPAR), and the 5-HT_1A receptor.

The endocannabinoid system (ECS) can be targeted to address breast, prostate and bone cancer and their accompanying pain syndromes. Additionally, the endocannabinoid system can produce anti-neoplastic effects in a number of other types of cancers, such as cancer of the skin, brain (gliomas), and lung.¹⁰

Studies have found that by removing the activity of the CB1 and CB2 receptors experimentally, a higher incidence of cancer will result. In mouse models of cancer, the genetic ablation of CB1 and CB2 receptors increases ultraviolet light-induced skin carcinogenesis. CB2 receptor (found mainly in the immune system) over-expression enhances predisposition to viral leukemia. CB2 receptors can be found on tumor cells.⁴

The pharmacological activation of cannabinoid receptors can reduce tumor growth. Upregulated endocannabinoid-degrading enzymes have been observed in aggressive human tumors and cancer cell lines, indicating that the presence and signaling action of endocannabinoids, and perhaps phytocannabinoids, can have a tumor-suppressive role.

When CB1 receptors have been deleted in a genetic mouse model of colon cancer, it was found that tumor growth was increased. Precancerous lesions in the mouse colon, induced by the chemical azoxymethane, could be reduced with increases in endocannabinoid levels. With the reduced expression of the endocannabinoid-degrading enzyme, monoacylglycerol (MAGL), prolonging elevated serum levels of endocannabinoids, tumor growth was inhibited in xenografted mice.

The precise signaling mechanisms that regulate cannabinoid-induced cell death or cell proliferation continue to be under investigation. We are still discovering the many details that will help to clarify the role the endocannabinoid system plays in tumorigenesis and tumor suppression.

Cannabinoids And Cancer

The anti-proliferative properties of cannabis were first reported 40 years ago when it was shown that THC inhibited lung adenocarcinoma growth in vitro and in vivo in mice. No other research resulted from this study for well over 20 years, due to the prohibition around the cannabis plant. In the last 20 years, though, we have seen an emerging body of investigation, mainly using in vitro models of different cancers, to further elucidate the mechanisms whereby the ECS has an impact on cancer cell proliferation, angiogenesis, and metastasis.

Since the late 1990s, following the discovery of the ECS, these studies have shown that the cannabinoids have an anti-tumor effect in a wide variety of experimental models of cancer. These studies have found that the pharmacological stimulation of CB receptors is anti-tumorigenic.¹

A number of cannabinoids (endo, Phyto and synthetic) have been shown to have this activity, including: 1) THC; 2) CBD; 2) 2-AG and anandamide; 3) Synthetic cannabinoid receptor agonists with equal affinity for both CB1 and CB2, such as WIN 55, 212-2, and HU-210; 4) Synthetic cannabinoid receptor agonists with a higher affinity for CB1 such as methandamide; and, 5) Synthetic cannabinoid receptor agonists with a higher affinity for CB2, such as JWH-133. The anti-neoplastic mechanisms of action of cannabinoids have been established through examination of the pharmacological impact of cannabinoid receptor agonists on tumor growth.^4 20

Randomized clinical trials with cancer patients who have naturally-occurring disease are still lacking from the literature, but there is sufficient evidence from these studies to say that the phytocannabinoids, THC and CBD, have been found to have activity against a number of tumor types: Breast, bone, glioma, leukemia/lymphoma, lung, colon, prostate, and thyroid.^10 16

Induction of Cancer Cell Death and Anti-Proliferative Effects⁴

The cannabinoids have been found to induce apoptosis by means of CB1 and CB2 stimulation of the synthesis of the pro-apoptotic sphingolipid, ceramide. In studies performed in vitro with THC-resistant and THC-sensitive glioma cells, it was found to upregulate the expression of the stress-regulated protein P8 (AKA: NUPR1). This protein is a transcription regulator and involved in the control of tumorigenesis and tumor progression. In these studies, THC also impacted the endoplasmic reticulum (ER) stress-related transcription factors ATF4, CHOP (AKA: DDIT3) and TRIB3.

ER stress response is an attempt by the endoplasmic reticulum to re-establish homeostasis. The stress response becomes activated in response to Ca⁺ depletion, oxidative injury, a high-fat diet, hypoglycemia, viral infections and exposure to certain anti-cancer agents. ER stress reduces the protein load on the endoplasmic reticulum by shutting down protein translation and gene transcription with the goal of increasing the ER protein-folding capability.

When this stress response fails to restore homeostasis, cell death can ensue, usually through intrinsic apoptosis, but through a different pathway can result in autophagy, which is another cause for cancer cell death. Autophagy is an attempt of the cell to correct its imbalance, and if successful, the cell will continue to live.

Autophagy is not always an effective path to cancer cell death. Interestingly, it has been found that autophagy is "upstream" to apoptosis in the mechanism of cannabinoid-induced cancer cell death. Blocking autophagy prevents cannabinoid-stimulated apoptosis, but apoptotic blockade prevents apoptotic cell death but not autophagy.

In addition to inducing cancer cell death through autophagy or apoptosis, cannabinoids also have been found to have an anti-proliferative effect by inducing cell cycle arrest. The effect of cannabinoids on hormone-dependent tumors may be due to their interference with activation of growth factor receptors. Cannabinoids can also down-regulate other cancer cell growth factors such as: PIGF, BFGF, SDF-1, Ang-2, leptin, interferon-γ, and thrombopoietin.

Cannabidiol, or CBD, is a cannabinoid that does not bind to CB1 or CB2 receptors directly, yet uses many alternate pathways to influence the endocannabinoid system. CBD has been observed to promote the apoptotic death of cancer cells, independent of CB1 and CB2 receptors. Its mechanism of action, which has not been completely worked out, promotes the production of reactive oxidative species in cancer cells as well as an increase in the other endocannabinoids through inhibition of FAAH and MAGL.

Inhibition of Angiogenesis, Tissue Invasion, and Metastasis⁴

The activation of the vascular endothelial growth factor (VEGF) pathway in cancer cells, is known to induce angiogenesis. It has been found that cannabinoids down-regulate the two main VEGF receptor (VEGFR1& VEGFR2) pathways through reduced production of VEGF. VEGFR activation is decreased as a result of the reduced amount of its ligand, VEGF. Activation of the CB receptors in vascular endothelial tissue inhibits proliferation and migration and induces apoptosis in addition to activating endothelial cells. Thus cannabinoid activity results in a more normalized tumor vasculature with smaller and/or fewer vessels that are less "leaky", therefore less likely to result in metastasis.

Cannabinoids have been found to reduce metastasis in animal models for glioma, breast, lung and cervical cancers grew in tissue culture. Tissue invasion, which is required for metastasis, is regulated by the extracellular proteases (MMP2) and their inhibitors (TIMP1), which are modulated by cannabinoids.

Clinical Use Of Cannabinoids In Cancer Patients

Although historical and anecdotal evidence suggests that cannabis can be used to treat clinical neoplastic disease, carefully-controlled clinical trials of cannabis as a cancer treatment are rare to non-existent. Currently, in the United States, THC and CBD are both considered to be Schedule One controlled substances. Researchers need a special Schedule One registration with the Drug Enforcement Agency of the United States to conduct research using these cannabis resins, and the only legal source of cannabis for clinical trials is the National Institute for Drug Abuse (NIDA), which makes the acquisition of these plant extracts difficult to obtain.

These factors all have made it difficult to conduct clinical studies into the effectiveness of cannabis for treating cancer. As a result, the preponderance of studies into the anti-neoplastic effects of cannabis have been in vitro or in vivo using experimental models for cancer in laboratory animals, versus clinical trials of patients with the disease.

Cannabinoids can express anti-neoplastic activity through binding with the CB1 receptor (This is for THC, anandamide, 2-AG). Phytocannabinoids other than THC (CBD, CBG, CBC, and others) do not bind to the CB1 or CB2 receptors but inhibit the enzymes (FAAH, MAGL) that degrade anandamide and 2-AG, thus causing prolonged binding of endocannabinoids to the cannabinoid receptors, which also has an anti-neoplastic effect.

The brain has the highest density of CB1 receptors in the body. Numerous studies in vitro and in animal models suggest that cannabinoids can inhibit gliomas.⁴ It has been found that other cancer cell lines are also inhibited by cannabinoids in vitro, such as adenocarcinomas of the lung, breast, colon, and pancreas, and also myeloma, lymphoma, and melanoma. Cannabis can enhance the activity of certain chemotherapeutic agents, and through the down-regulation of p-glycoprotein may also be able to reduce chemotherapy resistance.

The majority of studies evaluating cannabis in cancer patients have been to evaluate its ability to address symptoms of cancer or cancer therapies, such as pain, nausea, or anorexia. These studies have found that cannabis can work well for cancer pain. Cannabinoids have been found to work synergistically with concurrent opiate medication for better pain response in the cancer patient.¹³ One of the highest callings for medical cannabis in benefiting the cancer patient is its ability to control nausea, often better than the existing anti-emetic armamentarium.

The synthetic cannabinoid, dronabinol (Marinol™) was originally designed for this purpose and can work well, although it's a 100% synthetic THC analog, some persons taking it to report hallucinations. There is good evidence that plant-based cannabinoids work better to relieve nausea without the potential for adverse events. This is due to the tempering effect that a full-spectrum cannabis extract with its full complement of phytocannabinoids has on the psychotropic effect of THC.¹² Appetite stimulation is the third reason that cannabis has value to the cancer patient. Famous for creating "The Munchies", THC and CBD can help to relieve nausea and also increase appetite better than many of the existing aperient formulations.

Cannabis is the only anti-emetic that is also an appetite stimulant, although for anorexia-cachexia one study found it to be no better than placebo. This RCT was placebo-controlled to compare cannabis with the synthetic cannabinoid, dronabinol (Marinol™) in 243 human patients with the cancer-related anorexia-cachexia syndrome. It was found that there was no difference among any of the two treatments and the placebo with respect to affecting appetite or quality of life.¹⁴ Anecdotally, veterinary oncologists are observing that THC does not stimulate appetite in more than 50% of dogs, although this may be dose-dependent. Cats exhibit a better appetite response to THC.

Terpenes, which make up 10% of the total production of active molecules by the cannabis plant, are an integral part of the "Entourage Effect" that contributes to the clinical efficacy of cannabis. Certain terpenes, such as limonene has been shown to cause apoptosis of breast cancer cells. Additionally, for cancer pain, terpenes contribute substantially. Both phytocannabinoids and terpenes reduce inflammation and pain via inhibition of COX-2 and PGE2α.

Veterinary Cancer Patient Cannabis Considerations and Regulatory Issues

For the veterinary cancer patient, legal constraints to the use of THC must be accounted for in a reasonable and safe fashion. Veterinarians cannot prescribe or dispense THC. However, pet owners will come to a veterinarian asking for help using cannabinoids to treat their pet's cancer who have full access to state-legal dispensaries and the THC products they sell. The veterinarian should explain the risks and the problems with the current legal landscape, and the potential to send a patient to the ER with high doses of THC. The vet should explain that they cannot legally recommend or prescribe these Schedule One controlled substances. If the owner persists, then the veterinarian can give advice that will help to create a successful outcome free of unwanted side effects.

Studies in the 1970s discovered that dogs have a very high density of CB1 receptors in their hindbrain that govern balance and cardiovascular function.^8 9 This is why a few dogs who are naïve to THC, when exposed to a sufficiently large amount of THC, especially when in combination with chocolate, as is commonly found in human "edibles", have had reported deaths.¹⁹ These early studies found that dogs can develop tolerance to THC's adverse effects in about a week when THC is introduced in small amounts initially and gradually increased over time,. Once tolerance is achieved, dogs were able to handle escalated doses a 100 times higher than the original dose that had caused the adverse response in the first place. Once tolerance is developed, it would allow the canine patient to tolerate larger doses if their condition warranted it.

Studies²¹ and reports from human and veterinary oncologists, veterinarians, medical cannabis physicians, pet owners, and human cancer survivors, although anecdotal, indicate that the most successful approach to the use of cannabinoids in the cancer patient involves the oral use of a combined formula containing both THC and CBD, usually in a 1:1 ratio. This combination enhances the anticancer activity of the formula as these two cannabinoids have similar but different mechanisms of action against cancer, and work together synergistically.

Using a "ratio approach" to the blending of CBD with THC can help to reduce the dose of THC that is needed to inhibit tumor growth. The use of CBD also reduces the unwanted side-effects of THC, such as psychoactivity, convulsions, discoordination, and psychotic effects in humans and dogs, and in the dog, specifically, static ataxia.

The best approach to the blended use of THC and CBD from cannabis in a cancer patient is to use products that have THC and CBD formulated into a specific ratio of CBD: THC. Ratios can help to reduce the side-effects from THC and maximize the anti-neoplastic activity of the treatment. The protocol is to first start with cannabis that is hemp, which would have a ratio of CBD to THC of about 25:1.

The use of this small amount of THC present in the hemp will help to "tolerize" your patient to the larger doses of THC that will be used for anti-neoplastic effects in a 1:1 ratio of CBD: THC. CBD-dominant strains of cannabis with very low THC, but higher than hemp levels of THC can be used to increase the patient's tolerance to the higher doses of THC that are needed for cancer. Once the dog has been on the hemp for a week at a dose of 0.5-1.0 mg/kg BID of CBD, it should be tolerant of increases in its THC dosage, which will better address the anti-neoplastic effects of cannabis.

Starting dosages for the THC are also in the 0.1-0.5 mg/kg BID range, with the lower doses being less likely to cause adverse events. In this author's experience, patients who were taking 100% CBD for their tumors, with zero THC, would show an observed reduction in the size of the mass in about 6 weeks for that reduction to be substantial, as documented with photographs. The dose used in these successful cases was 0.5-1.0 mg/kg BID of CBD. Not all tumors respond to this dosage, but in those that do respond, it is remarkable to watch.

Summary

The available literature suggests that the endocannabinoid system can be targeted to suppress the evolution and progression of certain types of cancer and the pain, emesis and appetite syndromes associated with these diagnoses and treatments. In spite of the fact that there are no controlled clinical trials of cannabinoids in cancer patients as anti-neoplastic agents, there still is sufficient evidence to support the use of cannabinoids for veterinary patients with cancer in general, although specific tumor types may be more or less resistant to their beneficial effects. The biggest problem to date is the legal landscape since cannabinoids have been shown to be quite safe when given in controlled amounts.

Large population studies in humans have found no correlation between smoking cannabis and increased risk of respiratory symptoms/chronic obstructive pulmonary disease or lung cancer.¹⁷ Cannabinoids can be used concurrently with chemotherapy and have been found to not interfere with chemotherapy efficacy in the tumors and chemotherapy agents measured.¹⁵ Determining the effective dosage for an individual patient and tumor type will improve outcomes, and is work that still needs to be done.

Cannabinoids can induce autophagy, apoptosis, cell cycle arrest, reduce angiogenesis, tissue invasion and metastasis, without affecting normal cells. Cannabinoids can reduce pain, nausea and improve appetite. All of these actions make the use of cannabinoids for cancer very attractive to both the practitioner and the pet owner.

REFERENCES

1. Munson AE, Harris LS, Friedman MA, Dewey WL, Carchman RA. Antineoplastic activity of cannabinoids. Journal of the National Cancer Institute. 1975(55)3:597-602.
2. Herer J. The Emperor Wears No Clothes: Hemp and the Marijuana Conspiracy. Ah Ha Publishing, Van Nuys, CA. 1985
3. Guzman et al. Nature Medicine March 2000.??
4. Velasco G, Sanchez C, and Guzman M. Towards the use of cannabinoids as antitumor agents. Nature Reviews/Cancer. June 2012;12:436-444.
5. Salazar M, Carracedo A, Salanueva et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clinical Investigation; May 2009(119)5:1359-1372.
6. Thomas AA, Wallner LP, Quinn VP et al. Association between cannabis use and the risk of bladder cancer: Results from the California Men's Health Study. Urology 2015; 85:388-392.
7. Romano B, Borrelli F, Pagano E et al. Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol. Phytomedicine 2014; (21)631-639.
8. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC. Cannabinoid receptor localization in the brain. Proc Natl Acad Sci. 1990;87:1932-1936.
9. Martin BR, Dewey WL, Harris LS, Beckner JS. ³H–Δ⁹–Tetrahydrocannabinol tissue and subcellular distribution in the central nervous system and tissue distribution in peripheral organs of tolerant dogs. J Pharm Exper Ther.1976;196(1):128-144.
10. Guindon J and Hohmann AG. Review: The endocannabinoid system and cancer: Therapeutic implication. Brit J Pharm. (2011)163:1447-1463.
11. McAllister SD, Soronceanu L, Desprez PY. The antitumor activity of plant-derived non-psychoactive cannabinoids. J Neuroimmune Pharmacol. 2015;10:255-67.
12. Ben Amar M. Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol. 2006;105:1-25.
13. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain 2008;9:254-64.
14. Strasser F, Luftner D, Possinger K, et al. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multi-center, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J. Clin Oncol. 2006;24:3394-400.
15. Ward SJ, McAllister SD, Kawamura R, et al. Cannabidiol inhibits paclitaxel-induced neuropathic pain though 5-HT_1A receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol. 2014;171:636-45.
16. Massi P, Solinas M, Cinquina V, Parolaro D. Cannabidiol as potential anticancer drug. Br J Clin Pharmacology; 2012;75:303-312.
17. Tashkin DP. Smoked marijuana as a cause of lung injury. Monaldi Arch Chest Dis 2005;63:93-100.
18. Mosbergen D. Now We Know What Killed the Ancient "Ice Princess", and why she had that marijuana. [Web article]. The Huffington Post: http://www.huffingtonpost.com/2014/10/16/siberian-ice-princess-cancer-cannabis_n_5993052.html.
19. Meola SD, Tearney CC, Haas SA, Hackett TB, Mazzaferro EM. Evaluation of trends in marijuana toxicosis in dogs living in a state with legalized medical marijuana: 125 dogs (2005-2010) J Vet Emerg Crit Care;22(6)2012; pp.690-696.
20. Bifulco M, Laezza C, Pisanti S, & Gazzero P. Cannabinoids and Cancer: pros and cons of an antitumor strategy. Brit. J. Pharmcol. 2006;148:123-135.
21. Scott KA, Dalgleish AG, Liu WM. The Combination of Cannabidiol and Δ⁹-Tetrahydrocannabinoid Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model. Mol. Cancer Ther 2014;13(12);2955-67.

Copyright^© Dr. Robert J Silver