Marijuana (cannabis) and cancer - is there a connection and can it be legally used in Croatia?

What is marijuana anyway?

Marijuana (cannabis) originates from Central Asia and has been used for medicinal purposes for about 3,000 years. There are significant differences in opinions about the use of marijuana, but for now its use in Croatia is not legal, except for medical purposes on the recommendation of a competent doctor and for specific indications.

The cannabis plant produces a resin that, in addition to other compounds found in plants, contains the so-called cannabinoids. Cannabinoids are a group of carbon-containing compounds that are uniquely produced by the cannabis plant. Although delta-9-tetrahydrocannabinol (THC) is the primary psychoactive ingredient, there are other known compounds with biological activity such as cannabinol, cannabidiol (CBD), delta-8-THC and others. The highest concentration of cannabinoids is found in the female flowers of the plant. Although marijuana is often attributed medicinal properties by its supporters, clinical trials conducted so far are limited and marijuana has not been approved by leading health organizations for the treatment of any disease. It is important to distinguish some other terms. Hemp is a subspecies of cannabis that contains less than 0.3% THC. Hemp oil or CBD are products made from industrial hemp extracts (with a low THC content), while hemp seed oil is an edible fatty oil that is essentially free of cannabinoids. There are also various combinations of these products, as well as those with other herbal or other additives.

Can cannabis help me? Is the pharmaceutical industry silent on this?

The potential benefits of medical cannabis for cancer patients reported so far include antiemetic effects (anti-nausea), appetite stimulation, pain relief and improved sleep. Use in children is generally not recommended due to possible negative effects on brain development. CBD in particular is believed to have significant analgesic, anti-inflammatory and anxiolytic activity, without the significant psychoactive effects of THC. Before making a clear decision on whether cannabis can help cancer patients, one should critically examine the relevant scientific evidence, which is the only objective indicator of the answer to this question (all references are listed at the end of the text so that you can study them in more detail if you wish).

Laboratory studies and studies on animal models

First of all, it should be clarified that the results of studies conducted in laboratories and/or on animal models do not necessarily mean that the same results will be achieved in humans. Of course, positive results of such studies require additional studies on humans, but only after that can a final conclusion be drawn. It is very common for the results to not match (which is very well known in official medicine where only a small proportion of new drugs reach the market, among other things because some of them simply do not show efficacy in humans, although they previously showed positive results in animal models or in the laboratory), and therefore the results of this phase should be taken with great caution.

One study on mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors. During this two-year study, groups of mice and rats were given various doses of THC. A dose-related decrease in the incidence of hepatic adenoma and hepatocellular carcinoma tumors was observed in mice. A reduced incidence of benign tumors was reported in rats. In addition, 4 other studies have shown that other tumors are sensitive to growth inhibition caused by cannabinoids.

Cannabinoids can cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of invasion and metastasis. Cannabinoids seem to kill tumor cells, but not healthy ones, and may even protect them from cell death. For example, these compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats, while protecting normal glial cells of astroglial and oligodendroglial origin from CB1 receptor-mediated apoptosis.

In another mouse study, lung tumor growth was inhibited by 60% in mice treated with THC compared to control mice. However, one study with immunocompetent mouse tumor models showed immunosuppression and enhanced tumor growth in mice treated with THC.

Plant and endogenous cannabinoids have also been studied for their anti-inflammatory effects. Research in mice has shown that endogenous signaling of the cannabinoid system may provide protection against colon inflammation. As a result, the hypothesis has been developed that cannabinoids may be useful in reducing the risk and treating colon cancer.

CBD can also enhance the uptake of cytotoxic drugs into malignant cells. Activation of transient receptor potential vanilloid type 2 has been shown to overcome resistance to the cytostatic drug carmustine.

There are many more similar studies that are beyond the scope of this article.

Human Studies

When cannabis is ingested orally, peak plasma THC concentrations occur after 1 to 6 hours and remain elevated with a half-life of 20 to 30 hours. When taken orally, THC is metabolized in the liver to 11-OH-THC, a potent psychoactive metabolite. Inhaled cannabinoids are rapidly absorbed into the bloodstream with peak concentrations occurring within 2 to 10 minutes, declining rapidly over a 30-minute period and with little formation of the psychoactive 11-OH metabolite. Human studies are presented in several sections.

Cancer Risk with Cannabis Use

Studies conducted to date have provided conflicting evidence regarding the risks of various forms of malignancy associated with cannabis smoking.

A pooled analysis of three studies of men in northwest Africa (430 cases and 778 controls) showed a significantly increased risk of lung cancer among tobacco smokers who also inhaled cannabis.

A large retrospective study of 64,855 men aged 15 to 49 in the United States found that cannabis use was not associated with tobacco-related cancers and a range of common malignancies. However, the study found that among non-smokers, cannabis use was associated with an increased risk of prostate cancer.

A population-based study of 611 lung cancer patients found that chronic low-level exposure to cannabis was not associated with an increased risk of lung cancer or other cancers of the upper aerodigestive tract and found no positive associations with any type of cancer.

A systematic review of 19 studies that assessed premalignant or malignant lung lesions in people over 18 years of age who inhaled cannabis concluded that observational studies did not show statistically significant associations between cannabis inhalation and lung cancer.

Studies of the association between cannabis use and the development of head and neck tumors have also been inconsistent in their findings. A pooled analysis of nine studies by the US/Latin American International Consortium on Head and Neck Cancer included data from 1,921 cases of oropharyngeal cancer, 356 cases of tongue cancer, and 7,639 controls. Compared with never-smokers, cannabis smokers had an increased risk of oropharyngeal cancer and a reduced risk of tongue cancer. A systematic review of nine studies involving 13,931 participants also concluded that there was insufficient evidence to support or refute a positive or negative association between cannabis smoking and the incidence of head and neck cancer.

Three case studies reported an association between cannabis use and an increased risk of testicular cancer, particularly non-seminoma or mixed histology tumors. However, the sample sizes in these studies were inadequate to address the dose of cannabis. A study of 49,343 Swedish men aged 19 to 21 years who were followed for 42 years found no evidence of a significant association between cannabis use and the development of testicular cancer in those who had ever tried marijuana in their lifetime, but found that "heavy" cannabis use (more than 50 times in their lifetime) was associated with a 2.5-fold increased risk.

Analysis of 84,170 participants in the California study over 16 years of follow-up showed that 89 cannabis users (0.3%) developed bladder cancer compared with 190 (0.4%) men who did not report cannabis use. After adjusting for age, race, ethnicity, and body mass index, cannabis use was associated with a 45% reduction in the incidence of bladder cancer.

Overall, the conclusion is that although there are many cellular and molecular studies that provide strong evidence that inhaled marijuana is carcinogenic, the epidemiological evidence for a link between marijuana use and cancer is still inconclusive.

Cannabis Cancer Treatment

A search of PubMed, the world's leading database of scientific papers, found no adequately conducted clinical trials of cannabis as a cancer treatment in humans. Accordingly, there is currently no relevant scientific evidence that marijuana use could directly help treat any form of cancer. The only published trial of any cannabinoid in oncology patients is a small pilot study of intratumoral injection of THC in patients with recurrent glioblastoma, which did not show significant clinical benefit from such treatment. In a trial conducted in Israel, oral CBD was investigated in the treatment of recurrent solid tumors. The study is expected to be completed in 2015; however, the results have not been published. A small research study was conducted in the United Kingdom that used nabiximols (THC:CBD ratio 1:1) together with the cytostatic temozolomide in the treatment of patients with recurrent glioblastoma. The study included 21 patients, but the final results have not been published.

Does cannabis have side effects? What about addiction?

Marijuana advocates often claim that it is a "natural" plant and that as such it has no adverse effects on humans. However, this is not true. Since cannabinoid receptors, unlike opioid receptors, are not located in the areas of the brainstem that control breathing, fatal overdoses do not occur when using cannabis and cannabinoids as is possible with the use of opiates. However, cannabinoid receptors are present in other tissues in the body, and possible adverse effects include the following:

* Tachycardia (rapid heartbeat)

* Hypotension (low blood pressure)

* Conjunctival hyperemia (widening of blood vessels)

* Bronchodilation (widening of the airways)

* Muscle relaxation

* Reduced gastrointestinal motility.

Although cannabinoids are considered by some to be addictive drugs, their addictive potential is significantly lower than that of most other narcotics or substances. Withdrawal symptoms such as irritability, insomnia, restlessness, hot flashes, nausea, and cramps have been observed. However, these symptoms appear to be mild compared to withdrawal symptoms associated with opiates or benzodiazepines, and symptoms usually resolve after a few days. Unlike other commonly used drugs, cannabinoids are stored in adipose tissue and excreted at a slow rate (half-life of 1–3 days), and even abrupt cessation of cannabinoids is not associated with a rapid drop in plasma concentrations that would lead to more severe symptoms.

Since cannabis smoke contains many of the same components as tobacco smoke, there is a valid concern about adverse pulmonary effects. However, to date, occasional and low-cumulative cannabis use has not been associated with adverse effects on lung function.

Final conclusion

An overall level of evidence rating for the benefits of cannabis or cannabinoids cannot be assigned to cannabinoids because there simply has not been enough clinical research. Therefore, there is currently no evidence that cannabis could be a treatment for cancer patients.

Regarding cannabinoids, several controlled clinical trials have been conducted, and their analyses support the beneficial effect of cannabinoids (dronabinol and nabilone) on chemotherapy-induced nausea and vomiting compared to placebo. Therefore, these drugs are approved for use in this indication.

Regarding cannabis, ten clinical trials have been conducted on the use of inhaled cannabis in cancer patients. Four small studies evaluated antiemetic effects, but each investigated a different patient population and chemotherapy regimen. One study showed no effect, another study showed a positive effect compared to placebo, and the report of a third study did not provide sufficient data to draw a conclusion. Consequently, there is insufficient data to provide an overall level of evidence on the use of cannabis for chemotherapy-induced nausea. There are no published controlled clinical trials of the use of inhaled cannabis for other symptoms related to cancer or cancer treatment.

There is currently insufficient evidence to recommend cannabis inhalation as a treatment for cancer-related symptoms or symptoms associated with cancer treatment or side effects associated with treatment; however, further research is needed.

In accordance with the current approval in the Republic of Croatia, we at the onkologija.net team offer the possibility of prescribing cannabinoids for pain relief and for the relief of nausea and/or vomiting caused by chemotherapy. Contact us for more details!

References

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• Sanchez C. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res, 2001.

• McKallip RJ. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood, 2002.

• Casanova ML. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest, 2003.

• Blázquez C. Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res, 2004.

• Guzman M. Cannabinoids: potential anticancer agents. Nat Rev Cancer, 2003.

• Blazquez C. Inhibition of tumor angiogenesis by cannabinoids. FASEB, 2003.

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• McKallip RJ. Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol, 2005.

• Massa F. The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest, 2004.

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• Nabissi M. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis, 2013.

• Berthiller J. Cannabis smoking and risk of lung cancer in men: a pooled analysis of three studies in Maghreb. J Thorac Oncol, 2008.

• Sidney S. Marijuana use and cancer incidence (California, United States). Cancer Causes Control, 1997.

• Hashibe M. Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. Cancer Epidemiol Biomarkers Prev, 2006.

• National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press, 2017.

• de Carvalho MF. Head and neck cancer among marijuana users: a meta-analysis of matched case-control studies. Arch Oral Biol, 2015.

• Daling JR. Association of marijuana use and the incidence of testicular germ cell tumors. Cancer, 2009.

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