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Cannabinoids in medicine: 3-Part Series – Cancer, Pain, Arthritis

In the first of a series of five articles, Oxford Cannabinoid Technologies will discuss their expertise on the medicinal use of cannabis derivatives

This first piece will focus on the use of cannabinoids to treat cancer. The term ‘cannabinoid’ originally referred to a group of compounds found in the species of the cannabis plant known as Cannabis sativa.(1) Following the development of synthetic derivatives of cannabinoids and the discovery of natural endocannabinoids, the term ‘phytocannabinoid’ was given to cannabinoids obtained from cannabis plants.(2)

The best-known of these phytocannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD) and two well-known cannabinoid receptors in the brain are CB1 and CB2. The CB1 receptor binds with THC and is thereby responsible for THC’s psychotropic effects. Most if not all phytocannabinoids, however, act on more receptors than just these – the study of these compounds is, therefore, highly complex and their potential to treat a wide range of diseases is highly significant.

Cannabinoids and cancer

The potential of cannabinoids to alleviate the symptoms of cancer and even treat its underlying causes has been discussed since pre-clinical research papers in the early 1970s demonstrated that the growth of lung tumours in mice could be slowed by THC and other cannabinoids.(3) While the ability of cannabinoids to alleviate the symptoms of cancer is widely accepted, pre-clinical studies suggest that cannabinoids may be effective in the actual treatment of multiple cancer types (for instance glioblastoma multiforme((4)) and prostate cancer((5)). Some studies have also affirmed that cannabinoids have a protective effect against certain types of tumours. Others suggest that cannabinoids can inhibit proliferation, metastasis and migration of cancer cells and even induce their death.

Despite these potential anticancer effects of cannabis, it is also important to note that, depending on the drug concentration, studies have found that cannabinoids can both inhibit and stimulate cancer cell proliferation;(6) more research must, therefore, be undertaken on the effects of cannabinoids on different tumor cell types.

Anecdotal evidence

Beyond scientific studies, there have been several ‘real-world’ examples of cannabis having the potential to treat cancer:

  • In June 2018, the Coventry Telegraph and Birmingham Mail reported on Joy Smith, a cancer survivor, who was given six weeks to live when she was diagnosed with cancer in her stomach and bowel. Now, two years later, she is close to receiving the all-clear after taking regular doses of THC cannabis oil;(19)
  • In June 2018, the Express reported on Garry Hill, 83, who claims CBD oil helped to shrink his tumour by half. His doctor was “amazed” his cancer had shrunk, said Hill, who is now in remission;(20)
  • In April 2018, the Birmingham Mail reported on Lynn Cameron, who was given between six and eighteen months to live in 2013 after she was diagnosed with stage 4 brain cancer. When the doctors gave up, Lynn turned to CBD oil. Soon afterwards, her tumour started shrinking. By the sixth MRI, the cancer had gone;(21)
  • And in February 2018, the Daily Mail reported on Dee Mani, 44, who refused chemotherapy when she was diagnosed with triple negative breast cancer – deemed the most lethal form – and opted instead to try cannabis oil.Doctors gave her the all-clearjust five months after she did so.(22)

Given the growing body of pre-clinical research and anecdotal evidence, the potential curative properties of cannabinoids warrant significant further study. Cancer remains a key focus area for Oxford Cannabinoid Technologies, with multiple programmes already underway aimed at discovering new treatments for a range of cancer types. We look forward to sharing the learnings from these studies in due course.

References

1.) Mechoulam, R., (1967) Recent advances in the chemistry of hashish. Fortschr Chem Org Naturst 25:175–213.
2.) Pate, D. (1999) Anandamide structure-activity relationships and mechanisms of action on intraocular pressure in the normotensive rabbit model. PhD thesis, University of Kuopio, Kuopio, Finland.
3.) Munson, A., et al. (1975) Antineoplastic activity of cannabinoids. Journal of the National Cancer Institute.
4.) Velasco, G., et al. (2004) Hypothesis: Cannabinoid therapy for the treatment of gliomas? Neuropharmacology.
5.) Sarfaraz, S., (2005) Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Research.
6.) Bifulco, M., et al. (2006) Cannabinoids and cancer: pros and cons of an antitumor strategy. British Journal of Pharmacology.
7.) Preet, A. (2007) Δ9-Tet+rahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in-vitro as well as its growth and metastasis in-vivo. Oncogene 27:339. http://www.nature.com/onc/journal/v27/n3/abs/1210641a.html
8.) Olea-Herrero, N., et al. (2009) Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R (+)-Methanandamide and JWH-015: Involvement of CB2. British Journal of Cancer 101:940–950. https://www.nature.com/articles/6605248
9.) Preet, A., et al. (2011) Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prev Res (Phila) 4(1):65-75. http://www.ncbi.nlm.nih.gov/pubmed/21097714?dopt=Abstract
10.) Ramer, R., et al. (2012) Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. 26(4):1535-48. http://www.ncbi.nlm.nih.gov/pubmed/22198381?dopt=Abstract
11.) Scott, KA., et al. (2014) The Combination of Cannabidiol and Δ9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model. Mol Cancer Ther 10:1158/1535-7163. http://mct.aacrjournals.org/content/early/2014/11/12/1535-7163.MCT-14-0402
12.) Borrelli, F., et al. (2014) Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis 35(12):2787-97.
13.) Murase, R., et al. (2016) Suppression of invasion and metastasis in aggressive salivary cancer cells through targeted inhibition of ID1 gene expression. Cancer Lett 377(1):11–16.
14.) Hasenoehrl, C., et al. (2017) G protein-coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1. Int J Cancer 1:121-132.
15.) Ferro, R., et al. (2018) GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine. Oncogene 37(49):6368-6382.
16.) López-Valero, I., et al. (2018) Targeting Glioma Initiating Cells with A combined therapy of cannabinoids and temozolomide. Biochem Pharmacol 157:266-274.
17.) Barbado, MV., et al. (2017) Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo. Int J Cancer 3:674-685.
18.) Sulé-Suso, J., et al. (2019) Striking lung cancer response to self-administration of cannabidiol: A case report and literature review. SAGE Open Medical Case Reports 7:1-4.
19.) https://www.coventrytelegraph.net/news/coventry-news/cannabis-oil-cancer-claim-14390091;
https://www.birminghammail.co.uk/news/health/cancer-patient-says-cannabis-oil-14771799
20.) https://www.express.co.uk/life-style/health/970361/cancer-symptoms-lung-tumour-cbd-oil-cannabidiol
21.) https://www.birminghammail.co.uk/news/uk-news/cancer-survivor-praises-cannabis-oil-14341684
22.) https://www.dailymail.co.uk/health/article-5339261/Mother-44-cures-cancer-taking-cannabis-oil.html

Cannabinoids in medicine Part 2: Pain

October 11, 2019

In the second of a series of five articles, Oxford Cannabinoid Technologies will discuss their expertise on the use of cannabinoids in medicine

Following the first article that discussed the treatment of cancer, this second piece will focus on the use of cannabinoids to treat pain. Cannabinoids are active molecules found within the cannabis plant and include CBD and THC, two of the most notable cannabinoids currently being studied.

In the U.S. alone, the number of individuals suffering from chronic pain is close to 100m,1 with two-thirds of patients feeling that current medication does not meet their needs.2 More people suffer from chronic pain than cancer, heart disease and diabetes combined.3 Patients use cannabis to treat multiple forms of pain, with cannabis shown to address neuropathic (burning or lancinating), mechanical (dullness or aching) and inflammatory (acute or sharp) pain components or sensations.

Cannabinoid receptors are expressed in the peripheral and central nervous systems, as well as on immune cells. Pre-clinical data, in vivo animal model studies and a small number of clinical trials in acute, neuropathic, chronic and cancer pain models suggest that CB1 and CB2 receptors play an important role in pain processing and that modulation of the endocannabinoid system can alleviate pain.(4)

However, clinical trials have also shown that a thorough understanding of the interplay of various cannabinoids (e.g. THC vs. CBD)(5) and their specificity for different pain conditions, is essential to develop targeted pain medications that can help sufferers.

A growing body of research suggests that cannabis’ psychoactive ingredients may enhance the pain-killing effects of opiate drugs, allowing patients using cannabis to take lower doses of opiate medications. Research in JAMA Internal Medicine found that deaths associated with the use of opiate drugs fell in 13 states after medical cannabis laws were introduced.(6) Those states that permitted patients to consume medical cannabis saw a 24.8% drop in opiate-related overdoses over six years.

However, these findings have since been thrown into doubt following the publication of a recent paper which suggests that claims that the enactment of medical cannabis laws reduces opioid-related deaths should be met with cynicism.(7) The paper goes on to state that the association between these two factors does not hold when a more extensive data set from 2017 is analysed.

As cannabis continues to develop a foothold in the pain management market, product improvement cycles are likely to accelerate when research into individual cannabinoids becomes sufficiently advanced to allow the development of more personalised medicine. Current therapeutic options for patients living with pain are limited and consist predominantly of opioids and anti-inflammatory drugs. Over the years, it has become clear that the continued use of opioids has reached a crisis point in western economies, with many patients now dependent on these drugs. This fact, together with the large number of patients who do not react to the pain medication currently available on the market, highlights the need to develop additional methods of safer pain medication.

In drafted guidelines surrounding cannabis-based medicinal products published by NICE, the importance of collecting robust evidence regarding the long-term safety and effectiveness of medical cannabis was highlighted in order to remove barriers surrounding its prescription.(18) Rigorous, high-quality investigations into the use of cannabinoids in the treatment of pain are urgently required, as advised by The British Pain Society(19), in order for government policies surrounding the use of medical cannabis in pain treatment to be reformed and this, therefore, remains as one of Oxford Cannabinoid Technologies’ main areas of focus.

References

1 (2011) Institute of Medicine Report from the Committee on Advancing Pain Research, Care, and Education: Relieving Pain in America, A Blueprint for Transforming Prevention, Care, Education and Research. The National Academies Press. http://books.nap.edu/openbook.php?record_id=13172&page=1
2 A, Romero-Sandavol., et al. (2015) Peripherally restricted cannabinoids for the treatment of pain. Pharmacotherapy 35:917-925.
3 2017) American Academy of Pain Medicine AAPM Facts and Figures on Pain. Available from: http://www.painmed.org/patientcenter/facts_on_pain.aspx
4 Burston, JJ., et al. (2014) Endocannabinoid system and pain: an introduction. Proceedings of the Nutrition Society; Woodhams, SG., et al. (2015) The role of the endocannabinoid system in pain. Handbook of Experimental Pharmacology.
5 Alvarado-Vázquez, PA., et al. (2017) Cannabis and Cannabinoids for Chronic Pain. 5;19(11):67.
6 Bachhuber, MA., et al. (2014) Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med 174(10):1668-73.
7 Shover, C., et al. (2019). Association between medical cannabis laws and opioid overdose mortality has reversed over time. Proceedings of the National Academy of Sciences, 12624-12626.
8 Pinsger, M., et al. (2006) Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain—a randomized controlled trial. Wien Klin Wochenschr (11-12):327-35.
9 Blake, DR., et al. (2006) Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford) 1:50-2.
10 Abrams, DI., et al. (2007) Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology (7):515-21.
11 Pini, LA., et al. (2012) Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. J Headache Pain 8:677-84.
12 Naftali, T., et al. (2013) Cannabis induces a clinical response in patients with Crohn’s disease: A prospective placebo-controlled study. Clinical Gastroenterology and Hepatology 10:1276–1280.
13 Serpell M., et al. (2014). A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. European Journal of Pain, 999-1012.
14 Yassin, M. (2018) Effect of adding medical cannabis to analgesic treatment in patients with low back pain related to fibromyalgia: an observational cross-over single centre study. Clin Exp Rheumatol. Jan-Feb;37 Suppl 116(1):13-20.
15 Wu, J. (2018) Cannabinoid Type 2 Receptor System Modulates Paclitaxel-Induced Microglial Dysregulation and Central Sensitization in Rats. Pain pii: S1526-5900(18)30791-0.
16 Riva, N., et al. (2018) Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 18(2):155-164.
17 De Gregorio, D., et al. (2019) Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behaviour in a model of neuropathic pain. Pain 1:136-150.
18 https://www.nice.org.uk/news/article/nice-draft-guidance-and-nhs-england-review-highlight-need-for-more-research-on-cannabis-based-medicinal-products
19 https://www.britishpainsociety.org/static/uploads/resources/files/BPS_Position_Statement_on_the_medicinal_use_of_cannabinoids_in_pain_management.pdf

Cannabinoids in Medicine Part 3: Psoriasis and Rheumatoid Arthritis

January 7, 2020

Following the first two articles that discussed the treatment of cancer and pain, this third piece will focus on the use of cannabinoids to treat psoriasis and rheumatoid arthritis

Endocannabinoids, as well as several phytocannabinoids, have been shown to influence immune functions, regulating inflammation, autoimmunity, antitumourigenesis, antipathogenic responses and other processes.1 Numerous in vitro and in vivo studies have examined the therapeutic potential of cannabinoid signalling in inflammation-associated diseases (e.g. psoriasis) and attempted to dissect the complex immunological effects of cannabinoids.

Cannabinoids and psoriasis

Psoriasis is a chronic inflammatory disease of the skin, characterised by excessive proliferation of keratinocytes that results in the formation of thickened scaly plaques, itching and inflammatory changes of the epidermis and dermis.2 The underlying pathophysiology involves activation of classes of T-cells and their interaction with dendritic cells and other cells of the innate immune system, including neutrophils and keratinocytes.3

The following pre-clinical studies support the use of cannabinoids in the treatment of psoriasis:

A 2003 study in Journal of Clinical Investigation demonstrated that the cannabinoid receptors CB1 and CB2 are present in human skin cells, including keratinocytes;4

A 2003 study showed that anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation (abnormal keratinocyte differentiation is a hallmark of psoriasis);5

In 2004, a study in the Journal of Neuroimmunology used an in vivo mouse model to show that THC can shift the development of the predominantly pro-inflammatory T helper 1 (Th1) cell to the more anti-inflammatory (Th2) cell type profile;6

A 2007 study, published in the Journal of Dermatological Science, demonstrated that a range of cannabinoids inhibit keratinocyte proliferation in hyperproliferating human keratinocyte cell lines.7 The cannabinoids inhibited keratinocyte proliferation in a concentration-dependent manner. The activity of CBN (not significantly active at CB1/CB2 receptors) indicates more than one mechanism of action;

In 2011, a study using human cultured keratinocytes and a skin organotypic culture model, provided evidence that anandamide markedly suppresses keratinocyte proliferation and induces cell death, both in vitro and in situ. The cellular actions were mediated by CB1 and transient receptor potential vanilloid-1 (TRPV1). The cellular effects of anandamide are most probably mediated by Ca2+ influx and intracellular accumulation via the non-selective, highly Ca2+-permeable ion channel TRPV1. The study was published in the Journal of Investigative Dermatology;8

A 2016 study, published in the Annals of Dermatology, investigated the effect of CB1 agonists on mast cell activation. The authors found that CB1 agonists inhibited the release of inflammatory mediators and markedly and dose-dependently suppressed cell proliferation.9

Cannabinoids and rheumatoid arthritis

RA is one of the most prevalent autoimmune diseases and one of the main causes of disability globally, causing pain, joint malformation and joint destruction.10 Preliminary evidence suggests that cannabinoids have a role in the future treatment of RA.

In one study,11 protein and mRNA expression of endocannabinoids, AEA and 2-AG, and cannabinoid receptors, CB1 and CB2, were found in synovial tissue obtained from 13 patients diagnosed with RA and undergoing arthroplasty whilst synovial tissue obtained from healthy volunteers was negative for the same endocannabinoids. Another study of synovial tissue from patients with RA12 found that of inflammatory cytokines, IL-6 and IL-8, which are stimulated by synovial cells, were attenuated by low concentrations of the synthetic cannabinoid WIN 55,212-2.

Furthermore, three different research groups achieved improvement in mice with collagen-induced arthritis (“CIA”), following treatment with various cannabinoids;13 The use of cannabinoids for the treatment of pain associated with RA has been assessed in only one 2006 clinical trial, where 58 patients with RA were allocated either nabiximols or a placebo.14 Compared with placebo, patients treated with nabiximols exhibited decreased pain along with improved sleep quality.15

1 Oláh, A., et al. (2017) Targeting Cannabinoid Signalling in the Immune System: ‘High’-ly Exciting Questions, Possibilities, and Challenges. Front Immunol 8:1487.
2 Habif, TP. (2016) Psoriasis and other papulosquamous diseases. Clinical Dermatology. 6th ed. Philadelphia, PA: Elsevier 263-328.
3 van de Kerkhof, PCM and Nestlé, FO (2018) Dermatology. 4th Edition, By Bolognia, JL., et al. 8, Psoriasis 138-160.
4 Casanova, ML., et al. (2003) Inhibition of skin tumour growth and angiogenesis in-vivo by activation of cannabinoid receptors. J Clin Invest 111:43-50.
5 Maccarrone, M., et al. (2003) The endocannabinoid system in human keratinocytes. Evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activation protein-1, and transglutaminase. J Biol Chem 278:33896-33903.
6 Klein, TW., et al. (2004) Cannabinoid receptors and T helper cells. J Neuroimmunol 147:91-94.
7 Wilkinson, JD., et al. (2007) Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis. J Dermatolog Sci 45:87-92.
8 Tóth, BI., et al. (2011) Endocannabinoids modulate human epidermal keratinocyte proliferation and survival via the sequential engagement of cannabinoid receptor-1 and transient receptor potential vanilloid-1. J Invest Dermatol 5:1095-104.
9 Nam, G., et al. (2016) Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model. Ann Dermatol 28(1):22-9.
10 Shapira, Y., et al. (2010) Geoepidemiology of autoimmune rheumatic diseases. Nat Rev Rheumatol 6:468–476.
11 Richardson, D., et al. (2008) Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 10(2):R43.
12 Lowin, T., et al. (2016) The synthetic cannabinoid WIN55,212-2 mesylate decreases the production of inflammatory mediators in rheumatoid arthritis synovial fibroblasts by activating CB2, TRPV1, TRPA1 and yet unidentified receptor targets. J Inflamm 13:15.
13 Malfait, AM., et al. (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA 97:9561–9566; Fukuda, S., et al. (2014) Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis. BMC Musculoskelet Disord 15:275; Gui, H., et al. (2015) Activation of cannabinoid receptor 2 attenuates synovitis and joint destruction in collagen-induced arthritis. Immunobiology 220:817–822.
14 Blake, DR., et al. (2006) Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology 45:50–52.
15 Blake, DR., et al. (2006) Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology 45:50–52.

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