The SIO Research Committee is pleased to offer this fifth installment in a new blog series known as "Myths of Cancer".  In this series we will address some of the most common myths and misperceptions that arise around cancer risk and treatment related to diet and natural health products, as well as other complementary therapies such as yoga, acupuncture and meditation.  If you have a question you'd like us to address or comments about the this post, please send your suggestions to:  info@integrativeonc.org.  

 

We hope you enjoy the series!
Linda Carlson and Eugene Ahn, Research Committee 

Disclaimer: The opinions expressed in this blog series are the authors’ own, and not necessarily those of the Society of Integrative Oncology or the authors’ host institution(s)”

 

Does Cannabis Cure Cancer?

By Eugene Ahn, MD

Quick Answer Box

In cell cultures and animal models, cannabis-derived cannabinoids, particularly THC and cannabidiol, can have activity against some cancers (but paradoxically also accelerate the growth of others). But none of these studies provide evidence that cannabis can cure cancer (many drugs look great in cell cultures and animal models but fail in definitive clinical trials). There are two early phase clinical trials published, one of which suggests it is possible cannabinoids might help treat a very aggressive type of brain cancer with few side effects. But it is irresponsible and harmful to say cannabis cures all types of cancer. Research also shows alternative medicine use may delay conventional treatment, resulting in worse cancer-specific outcomes.  However, given its proven benefits helping treat cancer side effects such as loss of appetite, neuropathic pain, and nausea, it is reasonable to use as an integrative treatment for those indications, but not in lieu of conventional therapy, especially in curative intent situations.

 

I wish cannabis cured all cancers. I wish wishful thinking would make it true. As oncology health professionals, we are joyful when our patients are joyfully in remission, and we suffer when we see our patients suffer. If there is one thing we professionals have in common, it is that we welcome better cure probabilities and less side effects for our patients.

Over the past 18 years after having trained in both infectious diseases and oncology, I have taken care of many conditions that respond extremely well to cannabis or its psychoactive ingredient delta-9-tetrahydrocannibinol (THC), such as AIDS-related cachexia, chronic pain, nausea and loss of appetite from cancer or chemotherapy. I have also published case reports of extraordinary outcomes when they highlighted potential activity of an underappreciated intervention (for example, a case of Xeloda and graviola tea associated with a 5-year remission in a patient with metastatic breast cancer). I have a lot of patients who have utilized cannabis or its isolates in the hope it would cure their metastatic disease and assured them I would publish their case if they were successful. But I have yet to personally see a patient whose metastatic cancer went into miraculous remission with cannabis or cannabis products alone, although for most their quality of life was enhanced.

Dr. Donald Abrams, one of the earliest pioneers of cannabis research in supportive care, Professor of Clinical Medicine at University of California San Francisco and general oncologist at Zuckerberg San Francisco General Hospital, shared his clinical experience with medical cannabis in the state that first legalized it in 1996:

“As an oncologist in San Francisco for the past thirty-three years, I often say that I would venture to guess that the majority of the patients I have cared for have used cannabis during their treatment. Thus if cannabis cured cancer, I would have a lot more survivors. Granted, the plasma concentration of inhaled cannabis, as most of my patients have likely used in the past probably does not approach that which can be achieved with the highly concentrated oil preparations (no data available on this as of yet), but still, oncologists maintain that the plural of anecdote is not evidence! What saddens and disturbs me the most is when I see a patient in consultation with a potentially curable malignancy who is foregoing conventional cancer therapy in hopes that cannabis oil will be a kinder, gentler treatment. The fact remains that there is no evidence at this time to support such a decision.”

Dr. Abrams concludes, “That being said, what we do know is that cannabis is truly an amazing medicine for many cancer and treatment-related side effects — nausea, vomiting, loss of appetite, pain, depression, anxiety, insomnia.”

Dr. Abrams will be summarizing the scientific evidence of the benefits of cannabis and its isolates in an SIO webinar on Sept 13, 2018 in a way that only he can, having been on the leading edge of cannabis research in both HIV and cancer care. Not only will you learn about the science of cannabis, but also the sociopolitical challenges he navigated to research the plant’s benefits. I highly recommend signing up for this talk (link below) and it is free for SIO members and only $20 to register for non-members.

https://integrativeonc.org/news/sio-news/275-sio-webinar-september-13-12-30-1-30-pm-et

While cannabis is not a magic bullet for cancer, there is preclinical evidence in animal models and cell lines (cancer cells grown in petri dishes in the lab) to suggest cannabis might have an anti-cancer effect in humans. However, bear in mind that most drugs that perform similarly well in preclinical models turn out to not even shrink cancer or help people live longer when they are tested in definitive human trials.

To make sure the terminology in this blog is understood, allow me to run through a quick cannabis 101 review. The cannabis plant consists of primarily two species - C. sativa and C. indica - that contain more than 400 identified chemicals. For the sake of accuracy and relative simplicity, the relevant categories of its components are as follows:

Cannabinoids                                    Non-Cannabinoids
THC                                                    Terpenoids

Cannabidiol (CBD)                              Flavonoids

And over 100 others

Cannabinoids are defined as chemical compounds that interact with the cannabinoid receptors, which in humans include CB1, predominantly expressed on neurons in the brain and central nervous system, and CB2 expressed in non-neuronal tissues such as immune cells. Cancer cells can express these receptors as well, and studies are mixed as to whether it can indicate a better or worse prognosis compared to cells that do not have the receptors. But the effects of cannabinoids on cancer are not limited to interaction with these receptors as several studies have documented effects that are not prevented by blocking these receptors. THC is the cannabinoid classically associated with the psychoactive and appetite-stimulating effects, although it is not exclusively so. Cannabidiol is another cannabinoid that also has been studied for anti-cancer effects and is often referred to as CBD.

The FDA has approved several drugs that we will call cannabinoid-based (i.e. they are not naturally derived but synthetic): dronabinol (Marinol and Syndros, delta-9-THC), and nabilone (Cesamet, THC-similar). As of June 25, 2018, the FDA approved Epidiolex (cannabidiol naturally derived from cannabis) for two rare and severe forms of epilepsy, marking the first time a non-synthetic cannabinoid has been approved in the United States. However, the first regulatory approval for a naturally-derived cannabis product in North America was given by Health Canada for nabiximols (Sativex) for symptomatic relief of neuropathic pain (2005) and muscle spasticity (2010) from multiple sclerosis. Nabiximols is a formulated extract of C. sativa with a THC:CBD ratio of 1:1 as well as other cannabinoid and non-cannabinoid components.

Terpenoids and flavonoids are responsible for the color and aroma of plants and also serve biological functions. Relative to cannabinoids, these two categories of chemicals are not as well researched for their effects on cancer and will be omitted for brevity except when we discuss the entourage effect at the end of this blog.

Regarding anecdotal evidence (and yes, I count anecdotal evidence as evidence, just not of very high quality if it is not reliably reproduced in others) for anti-cancer effects of cannabis, the case that is most often brought up by my patients is that of Rick Simpson. From the information that is available on the internet, Rick was diagnosed with several basal cell carcinomas of the skin (not metastatic) and based on preclinical studies decided to treat his skin cancer topically with a concentrated cannabis oil and left a bandage on the lesions for several days. The lesions disappeared. I acknowledge this is a pretty impressive result but we still don’t know if that was a placebo effect (keep in mind it is also well known duct tape can cure warts but no more so than placebo), correlation not causation (did he or those who have followed suit receive any other intervention?), and even if the oil really was the cause of the remission at best we can say the oil might be worthy of research in the treatment of basal cell carcinomas.

But to extrapolate from this case (and the preclinical evidence) that cannabis oil is a suppressed cure for all types and stages of cancer is, at best, an innocent inference (educated guess) and, at worst, a delusion that has gone viral on the internet and is endangering the lives of patients with curable cancer who might choose to take cannabis oil in lieu of conventional therapy without any scientific follow up with imaging or surgery. However, Rick Simpson’s case report does warrant further research, especially after cell line and animal model research suggests that skin cancers can have inhibited angiogenesis (blood vessel growth) mediated by CB1 and CB2 receptors (Casanova et al).

To date, we only have two prospective clinical trials where a cannabis preparation or its derivatives was tested for an anti-cancer effect. Guzman et al conducted a phase I (preliminary trial to establish safety of the new intervention) and showed that intracranial administration of THC into an aggressive brain cancer called glioblastoma multiforme had antiproliferative effects in some of the 9 patients who received it, but all patients eventually progressed and died (though not due to the THC).

The second study (Twelves et al) is to date only published as an abstract, not a full paper (which means it hasn’t passed the gold standard of rigorous peer review). In this randomized, double blinded placebo-controlled study (meaning the investigators and patients were blinded as to whether they were getting the real cannabinoid preparation or placebo, which is generally considered the best way to minimize bias/confounding factors) patients with recurrent glioblastoma multiforme received either temozolomide (Temodar) chemotherapy and placebo or temozolomide with a 1:1 THC:CBD oro-mucosal spray, nabiximols (Sativex). Only 20 patients were intended to be enrolled in the randomized part of the study. Safety not tumor response was the primary objective, so these results are not reliable to make any definitive conclusions. Also requiring caution is that the study randomized 12 to THC:CBD and only 9 to placebo without any explanation of the discrepancy between study arms. In a small study like this, one patient can radically change the significance of the results. Median survival in the placebo group was 369 days and >550 days for the THC:CBD group and 1-year survival (meaning odds of being alive 1 year after entering the study) were 56% and 83%, respectively. The combination of nabiximols with temozolomide appears to be safe, but a larger phase II study is indicated.

Another hypothesis that has received a lot of attention is that cannabis has benefits on cancer that is maximized by an ‘entourage effect’, meaning that all the individual components of the plant work together to create an effect that’s greater than the effect of any one component. Blasco-Benito et al published in 2018 a study that compared the antitumor effects of THC alone compared to a whole plant extract and found that the extract was more potent than THC in cell culture and animal models of ER+, HER+ and triple negative breast cancer. Likewise, the extract was synergistic with tamoxifen, lapatinib and cisplatin chemotherapy in those respective cancer types. The authors also identified that the enhanced potency of the extract did not appear to be due to the 5 most abundant terpenes in the extract, consistent with the theory that the potency was due to the cannabinoid content. Does this study mean all patients with breast cancer should be taking cannabis extracts? Hardly. Remember that most drugs that have great looking data in cell cultures and animal models do not pass the bar of human clinical trials, with only 10% ultimately getting approved, with over 50% of the failed cases due to lack of efficacy (Hay et al). That said, this study and additional ones provide reassuring data for patients with cancer who choose to integrate cannabis with their conventional treatment to reduce side effects from cancer treatment. For example, numerous preclinical studies have tested whether there would be antagonism or synergy combining cannabinoids with chemotherapy agents. Briefly, in studies on cell cultures of pancreatic, glioma, gastric, lung and colon cancers using gemcitabine, temozolomide, paclitaxel and 5 fluorouracil, synergy is the common theme (reviewed by Maida et al).

However, not all cannabinoid research points to harmlessness as some cancer cells grow faster with exposure and there could be immunosuppressive effects to reckon with as well. When cannabinoids interact with the CB2 receptor, which if you remember is mainly expressed on immune cells, interferon gamma production is inhibited, T-cell proliferation is suppressed, and the immune system shifts from a Th1 to a Th2 profile, which is generally believed to be less conducive to an effective anti-cancer immune response. The relevant studies are reviewed well by other authors (Sledzinski et al).

Until we have evidence of how these findings would interact with any type of immunotherapy (i.e. PD1/PDL1 inhibitors like nivolumab) intervention, discernment in the use of cannabis is recommended. In fact, Taha et al conducted a retrospective observational study and reviewed the charts of 140 patients with advanced melanoma, non-small cell lung cancer and renal cell carcinoma who received nivolumab. 89 patients received nivolumab and 51 patients received cannabis with nivolumab. The authors found that the only significant factor that lowered the response rate to immunotherapy was cannabis (37.5% for nivolumab, 15.9% who received both (odds ratio 3.13; 95% CI 1.24-8.13, p=0.02). However, progression-free survival and overall survival was not effected by cannabis. Since this is a retrospective study and subject to numerous confounding factors, it is mainly a precautionary study that warrants additional research before making any definitive conclusions.

In conclusion, we know more than ever through scientific research what cannabis and its cannabinoid compounds can do, and with more research it is possible we might be able to establish therapeutic indications for cannabinoids for certain types of cancer. Please attend the upcoming webinar by Dr. Donald Abrams to see in more depth the clinical research that has helped de-stigmatize cannabis by documenting its benefits in improving the quality of life of patients dealing with cancer and cancer treatment-related symptoms. You will at least walk away with a greater appreciation for the role of research in helping individuals make more informed decisions for their health. If you read this blog too late or are unable to attend, Dr. Abrams has published several excellent articles that are listed at the end of the references below. As legalization of medical marijuana shifts across North America, more research will continue to reveal how we can best utilize cannabis or its isolates/derivatives for medical purposes, and likewise assure a future of less treatment side effects, better quality of life, and better cure probabilities.

References

  1. 1. Abrams DI. Cannabis and cancer - decoding the connection. San Fran Med 89(5): 28-29 2016
  2. 2. Guindon J and Hohmann AG. The endocannabinoid system and cancer: therapeutic implication. Br J Pharm 163: 1447-63 2011
  3. 3. Casanova ML, Blazquez C, Martinez-Palacio J et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111(1):43-50 2003
  4. 4. Guzman M, Duarte MJ, Blazquez C et al. A pilot clinical study of delta-9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 95:197-203 2006
  5. 5. Twelves C, Short S, Wright S et al. A two-part safety and exploratory efficacy randomized double-blind placebo-controlled study of a 1:1 ratio of the cannabinoids cannabidiol and delta-9-tetrahydrocannabinol (CBD:THC) plus dose-intense temozolomide in patients with recurrent glioblastoma multiforme (GB). J Clin Onc 35: 2046 (abstract) 2017
  6. 6.        Blasco-Benito S, Seijo-Vila M, Caro-Villalobos M, et al. Appraising the 'entourage effect': Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. Biochem Pharm published online 6/27/18
  7. 7. Hay M, Thomas DW, Craighead JL et al. Clinical development success rates for investigational drugs. Nature Biotechnology 32:40-51 2014)
  8. 8. Taha T, Talhamy S, Wollner M, et al. The effect of cannabis use on tumor response to nivolumab in patients with advanced malignancies. Oral presentation at: ESMO 2017 Congress; Abstract 1545PD 2017
  9. 9. Maida V, Daeninck PJ. A user's guide to cannabinoid therapies in oncology. Curr Onc 23(6): 398-406 2016
  10. 10. Sledzinski P, Zyeland J, Slomski R et al. The current state and future perspectives of cannabinoids in cancer biology. Cancer Med 7(3): 765-75 2018
  11. 11. Abrams DI. Using medical cannabis in an oncology practice. Onc J 1-4 2016
  12. 12. Abrams DI. Integrating cannabis into cancer care. Curr oncol 23(S2):S8-14 2016
  13. 13. Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharm Ther published online 2015