Cannabis and cancer management 

Screen Shot 2018-07-03 at 12.08.24The dried buds and leaves of varieties of the Cannabis sativa plant has been used in herbal remedies for centuries. Scientists have identified many biologically active components called cannabinoids, the two most studied are the chemicals and cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) the later having the psychotropic (high) effects responsible for its popularity. As a natural plant based product it also contains numerous other polyphenols and phytochemicals which as a group have numerous reported health benefits [Thomas].

When cannabis is eaten between 6%–20% of the cannabidiols become bioavailable with 1- 6 hour but can stay in the blood stream for up to 30 hours. Inhaled cannabis great has a peak serum level within 2-30mins declining rapidly within an hour and has less generation of the psychoactive metabolite [Adams, Agurell].

There is enormous interest in the media and within advocacy group blogs based on anecdotal reports of miraculous responses and cures. Most relating to cancer  are unsubstantiated, exaggerated or failed to mention concomitant medical treatments which were likely to have the main influence on the responses. That said, there are very few well conducted studies evaluating its anti-cancer effect and there are a number of possible reasons for this:

First, its illegal status has thrown substantial bureaucratic barriers to designing trials evaluating an anti-cancer effect. Second, as a plant product, it is difficult to circumnavigate the rules of licencing organisations such as the MHRA and FDA who require precise levels of active ingredients. For most plant based products sources from various farms across the World it is difficult to achieve this. Companies such as GWpharma, who have conducted the trials on multiple sclerosis and epilepsy grow their crops in heavily guarded hermetically sealed biospheres; the seeds, soil, nutrients, water and light have to be identical for each crop and even then, they have to measure the levels of THC and CBD and only select the plants within a strict concentration band – This level of technology is outside the abilities of most companies. The final and probably most important point. Cannabis itself cannot be patented or intellectually protected so that pharmaceutic companies are reluctant to invest millions of dollars in trial development when the results could just be copied the product made by rival companies. Despite these barriers, there are some published studies, particularly looking at its benefit as a supportive agent to help symptoms of disease and treatments.

Recreational cannabis use

Screen Shot 2018-07-03 at 12.08.33Cannabis goes by many names, including marijuana, pot, grass, cannabis, weed, hemp, hash, ganja, and dozens of others. Although in some parts of the World it’s recreational use is legal is the most widely used illegal drug. The effects of cannabis vary from person to person:

  • users may feel chilled out, relaxed and happy
  • some people get the giggles or become more talkative
  • hunger pangs (“the munchies”) are common
  • colours may look more intense and music may sound better
  • time may feel like it’s slowing down

Cannabis can have other, negative, effects too particularly with stronger forms of cannabis:

  • Unaccustomed users may feel faint or sick
  • it can make users sleepy and lethargic
  • it can affect memory
  • it makes some people feel confused, anxious or paranoid,
  • some experience panic attacks and hallucinations
  • it interferes with the ability to drive safely
  • regular users, may get demotivated and uninterested in education or work.
  • long-term use can affect the ability to learn and concentrate.
  • about 10% can get addicted particularly if users start using it in their teens
  • it may encourage users to chance the euphoric effect with stronger more harmful drugs
  • withdrawal can lead to insomnia, mood swings irritability and restlessness.
  • smoking cannabis risks bronchitis, coronary heart disease.
  • regular and early cannabis use increases the risk as schizophrenia.
  • regular use reduces sperm count in men and ovulation in women

 

Cannabis and cancer – is there an increased risk

A number of studies have yielded conflicting evidence regarding the risks of various cancers associated with cannabis smoking but most have concluded there is no increased risk if the influence of tobacco was excluded [Berthiller]. For example, the large, cohort study of 64,855 men from the United States found that cannabis use was not associated with tobacco-related cancers [Sidney]. Another  population-based study of lung cancer patients revealed that chronic exposure was not associated with an increased risk of oralpharyngeallaryngeal, lung or oesophagus cancer when adjusting for several confounders [Hashibe]. A systematic review of observational studies failed to demonstrate statistically significant associations between cannabis inhalation and lung cancer and finally a meta-analyses, the National Academies of Sciences, Engineering, and Medicine report concluded that there was no statistical association between Cannabis smoking and lung cancer [National].

Chronic marijuana use does use produces effects on the endocrine and reproductive system. Three population-based case-control studies reported an association between cannabis use and slightly elevated risk of germ cell or testicular cancers [Daling, Trabert, Lacson]. This was confirmed in a study of 49,343 Swedish men enrolled in the military then followed up for 42 years. Although it did not affect infrequent users heavy cannabis use (more than 50 times in a lifetime) was associated with a 2.5-fold increased risk [Callaghan].

Cannabis and cancer – evidence for a treatment effect 

Screen Shot 2018-03-25 at 12.52.59The California Men’s Health Study followed 84,170 participants for 16 years and found that cannabis users developed a small but statistically significantly lower number of bladder cancer compared to non-users [Thomas].

In animal studies, cannabis extracts, like other polyphenol rich products, have demonstrated anticancer properties of THC and other cannabinoid agonists. The mechanism of action included activation of pathways that leads to the stimulation of apoptosis; inhibition of VEGF leading to inhibit tumour angiogenesis; and decrease cancer cell migration reducing invasion into adjacent tissues and metastasis. Two major endocannabinoid-specific receptors have been identified andandamine and 2-arachidonoyllglycerol (2-AG) These are over-expressed in several types of tumours including glioblastoma multiforme (GBM), and higher grade prostate and colon cancers.  Researchers are suggesting that future studies measure these receptors levels and give cannabolids only to people who tumours over express them [Guzman, Velasco, Pisanti].

Despite these promising laboratory studies, there is little evidence, so far, for a significant, benefit in humans.  One small pilot study gave intratumour injections of delta-9-THC in patients with recurrent but there was no significant clinical benefit [Guzmán]. A number of other ongoing trials are giving oral cannabidiol (CBD) to patients with recurrent solid tumours on its own, in combination with chemotherapy but at the time of writing this section they had been recruiting slowly and have not been reported. In view of the synergy with a chemotherapy for brain tumours (temozolomide) seen in animal studies, there is particular interest in the investigation of nabiximols (with a 1:1 ratio of THC:CBD) in conjunction with temozolomide in patients with recurrent glioblastoma multiforme. Some case studies have been published reporting good responses for topical application of cannabis oil for a type of skin cancer called basal cell carcinoma but further long term randomised studies are required before this becomes confirmed and added to routine management.

Interference with cancer treatments:  

Cannabinoids are known to potentially interact with the liver enzyme cytochrome P450 but in one small study, patients treated with irinotecan or taxotere , addition of cannabis tea did not significantly influence exposure to and clearance of the chemotherapy [Engels].

Anti-sickness (Antiemetic) effects

Dronavinol and Nabilone both containing synthetic delta-9-THC, are approved for cancer related nausea since 1982 [Sutton]. A Cochrane meta-analysis of 23 subsequent randomized RCTs reviewed studies showed that, either as on their own (monotherapy) or in combination with other antiemetics, individuals were more likely to report complete absence of nausea and vomiting when they received cannabinoids compared with placebo, although they were more likely to withdraw from the study because of an adverse event such as sedation, or drowsiness, dizziness, dysphoria or depression, hallucinations, paranoia or hypotension [Ahmedzai, Smith]. Since these studies newer very effective anti-emetics are available such as ondansetron and aprepitant with less side effected making the role of cannabaloids are less relevant.

Appetite Stimulation

Small studies have shown THC increased appetite in patients with AIDs compared to placebo [Biel]. Three other studies have showed it was slightly inferior to progesterone called megestrol another appetite stimulator [Jatoi]. In trials conducted in the 1980s that involved healthy control subjects, inhaling cannabis increase in caloric intake, although mainly in the form of between-meal snacks, with increased intakes of fatty and sweet foods [Strasser, Foltin].  No published studies, to date, have explored the effect of inhaled cannabis on appetite in cancer patients.

Analgesia, anxiety and sleep

One small study reported that cannabinoid delta-9-THC was associated with substantial analgesic effects, with antiemetic effects, relaxation benefits and appetite stimulation [Abrams]. In a follow up  study, 10 mg doses of delta-9-THC produced analgesic effects for 7 hours comparable to 60 mg doses of codeine, and 20 mg doses of delta-9-THC induced effects equivalent to 120 mg doses of codeine [Wilsey]. Another study reported that patients who used nabilone experienced improved management of pain, nausea, anxiety, increased quality of sleep and relaxation when compared with untreated patients, resulting in decreased use of opioids, anti-inflammatory drugs, anti-depressants, gabapentin and anti-sickness drugs [Wilsey].  Patients often experience mood elevation after exposure to cannabis and depending on their previous experience could be positive or negative. A five-patient series of inhaled Cannabis  reported that patients who self-administered Cannabis had improved mood, improved sense of well-being, and less anxiety[Noyes].

Peripheral neuropathy (neuropathic pain)

Two RCTs of inhaled cannabis in patients with peripheral neuropathy or neuropathic pain of various aetiologies found that pain was reduced compared with those who received placebo [Hohnsom, Lynch]. Two additional trials of inhaled cannabis have also demonstrated a benefit over placebo in HIV-associated neuropathic pain [Maida, Wilsey].

In conclusion

Cannalaboids have a useful role in cancer management if used wisely and patients monitored closely. There is reasonable evidence of a benefit for neuropathic pain, other pains, appetite stimulation and nausea but some patients have troublesome side effects. There are laboratory data to suggest anti-cancer benefits and one population study linking a lower risk of bladder cancer. Evidence for a direct anticancer benefit in humans, outside anecdotal reports, is lacking although studies are ongoing.


References

  1. Adams IB et al Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996.
  2. Thomas R et al.  Phytochemicals in Cancer Management. 2017 Current Research in Compl and Alt therapy 105, 01.
  3. Agurell S et al.: Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38 (1): 21-43, 1986.
  4. Engels FK, de Jong FA, Sparreboom A, et al.: Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel. Oncologist 12 (3): 291-300, 2007.
  5. Berthiller J et al.: Cannabis smoking and risk of lung cancer in men: a pooled analysis of three studies in Maghreb. J Thorac Oncol 3 (12): 1398-403, 2008.
  6. Sidney S et al.: Marijuana use and cancer incidence (California, United States). Cancer Causes Control 8 (5): 722-8, 1997.
  7. Hashibe M et al.: Marijuana use and the risk of lung Cancer Epidemiol Biomarkers Prev 15 (10): 1829-34, 2006.
  8. National Academies of Sciences, Engineering, and Medicine: The Health Effects of Cannabis and Cannabinoids: The National Academies Press, 2017.
  9. Daling JR Association of marijuana use and the incidence of testicular germ cell tumors. Cancer 115 (6): 1215-23, 2009.
  10. Trabert B, et al.: Marijuana use and testicular germ cell tumors. Cancer 117 (4): 848-53, 2011.
  11. Lacson JC et al.: Population-based case-control study of recreational drug use and testis cancer risk Cancer 118 (21): 5374-83, 2012.
  12. Callaghan RC et al.: Cannabis Use and Incidence of Testicular Cancer: in Swedish Men between 1970 and 2011. Cancer Epidemiol Biomarkers Prev 26 (11): 1644-52, 2017.
  13. Thomas AA et al.: Association between cannabis use and the risk of bladder cancer: results from the California Men’s Health Study. Urology 85 (2): 388-92, 2015.
  14. Pergam SA et al.: Cannabis use among patients at a comprehensive cancer center in a state with legalized medicinal and recreational use. Cancer 123 (22): 4488-4497, 2017.
  15. Guzmán M, et al.: A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 95 (2): 197-203, 2006.
  16. Velasco G et al: Towards the use of cannabinoids as anti-tumour agents. Nat Rev Cancer 12 (6): 436-44, 2012.
  17. Sutton IR: Cannabinoids in the management of intractable chemotherapy-induced nausea and vomiting and cancer-related pain. J Support Oncol 4 (10): 531-5, 2006
  18. Ahmedzai S , et al.: Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. Br J Cancer 48 (5): 657-63, 1983.
  19. Hesketh PJ, Kris MG, Basch E, et al.: Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 35 (28): 3240-3261, 2017.
  20. Tramèr MR et al.: Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 323 (7303): 16-21, 2001.
  21. Ben Amar M: Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol 105 (1-2): 1-25, 2006.
  22. Smith LA et al.: Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev (11): CD009464, 2015.
  23. Jatoi A et al.: Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: J Clin Oncol 20 (2): 567-73, 2002.
  24. Strasser F et al: Comparison of orally cannabis in patients with cancer-related anorexia-cachexia: a multicenter, double blind phase III, RCT. J Clin Onc 24 (21): 3394-400, 2006.
  25. Beal JE, et al.: Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 10 (2): 89-97, 1995.
  26. Foltin RW: Behavioral analysis of marijuana effects on food intake in humans. Pharmacol Biochem Behav 25 (3): 577-82, 1986.
  27. Johnson JR, et al.: Long-term safety and tolerability of THC/CBD oromucosal spray in patients with terminal cancer-related. J Pain Symptom Manage 46 (2): 207-18, 2013.
  28. Lynch ME, C: A double-blind, placebo-controlled, cannabinoid extracts for chemotherapy-induced neuropathic pain. J Pain Symptom Manage 47 (1): 166-73, 2014.
  29. Maida V et al.: Adjunctive nabilone in cancer pain and symptom management: J Support Oncol 6 (3): 119-24, 2008.
  30. Wilsey B, Marcotte T, Deutsch R, et al.: Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 14 (2): 136-48, 2013.
  31. Wilsey Bet al.: A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 9 (6): 506-21, 2008.
  32. Noyes R Jr and Baram DA: Cannabis analgesia. Journal of Compr Psychiatry 15 (6): 531-5, 1974.
  33. Pisanti et al  The endocannabinoid signaling system in cancer Trends Pharmacol Sci, 34 (5) (2013), pp. 273-282
  34. Velasco G. Use of cannabis as an anticancer agent Process in psychosocial pharmacology and psychiatry 2016, 64, 259-66