Cannabinoids and Cancer
There is an increasing body of knowledge and a number of studies emerging investigating the use of cannabinoids in cancer care both for symptom management and as an anticancer agent itself. It remains a controversial area and in Australia its medical use has been approved for palliation and terminal care. In other countries, mostly European and an increasing number of areas in North America, it is being legalised for both recreational and medicinal use. It is one of the questions most often asked of integrative practitioners and professional attitude has been evolving over the past two decades from that of opposition and stigmatisation to that of consideration.
Cannabinoid Chemistry and Biologic Effects
Anandamide (Sanskrit for “bliss”) is the cannabinoid naturally occurring in the body (endocannabinoid) and acts via cannabinoid receptors type 1 (CB1) and type 2 (CB2). CB1 is located in the central nervous system (CNS), namely concentrated in the basal ganglia, cerebellum, hippocampus and cerebral cortex and also in the peripheral nervous system (PNS). It is also present in all body tissues. CB2 is mostly located in the immune system including macrophages, the marginal zone of the spleen, B lymphocytes and NK cells. The cannabis plant contains two main components that resemble the endocannabinoid and are responsible for its biological activity in humans. Delta-9-Tetrahydrocannabinol (THC) is the main psychoactive component and Cannabidiol (CBD) modulates the effects of THC.
Pharmacology
Cannabis is typically ingested or inhaled. Ingested, it has low and variable bioavailability with a peak plasma concentration after 1 – 6 hours which remains high with a half-life of 20-30 hours. Inhaled, it is rapidly absorbed with a peak concentration after 2 – 10 minutes and declines over the following 30 minutes. It is metabolised in the liver and interacts with the cytochrome P450 enzyme system which needs to be considered when liver contraindications are present such as liver failure and in liver cancer.
Symptom Management in Cancer
Cannabis is being increasingly studied for use in cancer care and has been thought to have value in the following areas:
1. Nausea and Vomiting
Tramer et al (2001) published a systematic review of 30 RCTS including 1366 participants. It found cannabis to be significantly more effective for treating cancer-related and chemotherapy-induced nausea and vomiting than the majority of antiemetics used in cancer including prochlorperazine (common brand name Stemetil), metoclopramide (common brand name Maxolon), chlorpromazine (common brand name Largactil), haloperidol (common brand name Haldol) and domperidone (common brand name Motilium). However, this was not the case at the extremes, that is in the presence of very low or very high levels of nausea. Reported side effects included euphoria, sedation, drowsiness, dizziness, dysphoria, depression, hallucinations, paranoia and hypotension. Amar et al (2006) showed that patients favoured using cannabis over other anti-emetics however not over serotonin receptor antagonists (chlorpromazine aka Largactil). It is very important to note that side effects limited its use at times and that the inhaled version was not as effective as the ingested (i.e effective 25% of the time) and was associated with more hallucinations and distorted time perception.
2. Appetite and Weight Loss
Small trials have suggested that cannabis stimulates appetite and may slow weight loss. It is thought to enhance chemosensory perception by way of the CB1 receptors in the hypothalamus. This enhances the motivational and reward aspects of eating. However, whether this translated clinically is yet to be seen. It has been shown to improve appetite but has not been shown to improve weight or reverse cancer cachexia which is a function of energy wasting as well as a reduction in food intake. An RCT of 469 participants compared its use with progesterone and found it was not superior for improving appetite and weight loss. The theoretical advantage is that the majority of antiemetics do not necessarily improve appetite and cannabis is an agent with the potential to do both and address two of the most common symptoms experienced in cancer.
3. Pain Control
A commonly reported area of effectiveness is in pain control. Cannabis is thought to produce its analgesic effects via the CB1 receptor in the CNS and both CB1 and CB2 in the periphery. It also has an anti-inflammatory component responsible for pain relief. It acts on mast cells via CB2 to attenuate the release of the inflammatory agents histamine and serotonin and on keratinocytes to enhance the release of analgesic opioids. It is also thought to have additive effects with opioids and cannot be blocked by opioid antagonists. THC activates kappa and delta opioid receptors and induces synthesis and release of endogenous opioids.
Trials of the use of CBD in cancer pain are sparse. There are numerous animal studies, however, early human studies showed a possible hyperalgesic effect. Small trials by Noyes et al (1975) showed some pain response, however higher doses were associated with sedation higher than that of opioids. Johnson et al (2010) conducted an RCT of 177 patients with opioid-resistant pain comparing THC with THC and CBD in combination and placebo. Results showed the combination of THC and CBD to be superior to placebo by 30% but THC alone was equivalent to placebo.
4. Neuropathy
Nerve pain is also a common experience in cancer either due to direct invasion of the cancer into the nerve, nerve injury from cancer treatment or chemotherapy induced peripheral neuropathy. Inhaled cannabis has been shown to improve neuropathic pain in HIV and Multiple Sclerosis (MS) by using THC and CBD in combination over using CBD alone. And an animal model has shown CBD to prevent paclitaxel-induced neurotoxicity.
5. Anxiety, Depression and Sleep
Cannabis produces euphoria and elevated mood in some and in others it produces dysphoria with or without paranoia. In those for whom it produces dysphoria with or without paranoia, it is not likely to be clinically useful. It is also known to produce sleepiness.
Role as an Anticancer Agent
Most of the evidence for cannabis as an anti-cancer agent comes from cell culture systems and animal models. THC is thought to be the anti-cancer agent and CBD is thought to enhance its effect. THC exerts its anti-cancer effect by modulating signalling pathways that lead to growth arrest, cell death and inhibiting angiogenesis and metastasis. This has been seen in cell lines for glioma, thyroid, lung adenocarcinoma, epithelioma, leukaemia, lymphoma, neuroblastoma, skin, uterus, breast, gastric, colorectal, pancreatic and prostate cancer. Cannabinoids also appear to kill cancer cells but leave normal cells unaffected and they have also been shown to enhance the effects of chemotherapy in laboratory studies of glioma xenografts.
Cannabinoids and Cancer Risk
Population studies have shown mixed results about whether the use of cannabis increases the risk of developing cancer in for example, recreational users. Some suggest an increase in lung, oropharyngeal, prostate and cervical cancers whereas others show it to be possibly protective, reducing the risk of lung, oral, oesophageal, larynx and pharynx cancers. There is however, one area worth following as three separate trials have suggested a possible link to testicular cancer especially the non-seminomatous germ cell tumours.
Safety and Side Effects
Cannabis is most commonly known for producing euphoric effects however, it is also associated with numerous other undesirable effects including:
Sensory: temporal and spatial perception alteration and disorientation
Somatic: drowsiness, dizziness, motor incoordination
Cognitive: confusion, memory lapse, difficulty concentrating
Peripheral: tachycardia, hypotension, conjunctival injection, bronchodilation, muscle relaxation, reduced gastrointestinal motility
The CBD component modulates the undesirable effects of THC including anxiety, seizures, psychoses, motor coordination, anticholinergic and immunosuppressive effects.
The effects are largely individualised and can be dose dependent. There is also evidence to suggest an adverse impact on fertility and reproduction. Cannabis is associated with dependence, tolerance and withdrawal (irritability, insomnia, restlessness, hot flushes, nausea, cramping), however, overdose is typically unlikely.
The combination of THC with CBD appears to be beneficial to maximise the benefits of each. In some, the undesirable effects may limit the use of cannabis for any symptom management in cancer and for those it is not advisable as there can be alternative agents of more benefit with less detriment. The benefits appear to be superior in ingested form (ie tincture or liquid capsule form) over the inhaled or edible form.
Recommendations
Cannabis appears most effective for caner-related nausea and pain. It should be reserved for when other agents and options have either failed, symptoms have become resistant to those agents or adjuncts are necessary. Consultation with a professional in the field and the conventional medical team is essential for proper titration and to avoid interference with other medications as well as to elucidate any contraindications. A clean, pure, organic source that has not been interfered with is important. It appears to be highly beneficial in palliative and terminal settings and is worth considering in such scenarios. There is not sufficient evidence to recommend its clinical use as an anti-cancer agent at present although theoretical and in vitro studies are encouraging and is an area worth following.
References
Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol Ther. 2015;97(6):575-586. doi:10.1002/cpt.108
