Cannabinoids in treatment of side effects from cancer chemotherapy

Overview

The use of cannabinoids in treating the side effects of cancer chemotherapy is more widely-studied than other potential therapeutic applications and a number of clinical studies have taken place investigating the use of THC and synthetic cannabinoids as anti-emetic agents. Two preparations have been licensed for use in clinical treatment either in the UK or elsewhere, including dronabinol (synthetic THC) and Nabilone (a novel synthetic cannabinoid).

The powerful drugs used in cancer chemotherapy effectively kill reproducing cells, including both the malignant tumour cells and also, as a side effect, many cells continually reproducing such as hair follicle cells and those lining the gut, leading to severe nausea & vomiting. These side effects can be very severe and many patients find these difficult or impossible to tolerate, falling into a wasting syndrome through malnutrition brought on by a combination of reduced appetite and poor gastrointestinal efficiency, which can itself shorten life expectancy.

There is variation between the effects of different anti-cancer drugs. Cisplatin, one of the most effective chemotherapy agents, induces vomiting in over 99% of patients not taking an antiemetic, with around 10 vomiting episodes per dose, although methotrexate causes emesis in under 10% of patients

There are also variations in the efficacy and side effects between conventional drugs used to treat nausea and vomiting. The BMA listed the side effects of commonly-used anti-emetic drugs as follows:

Phenothiazines (prochlorperazine, haloperidol) - severe dystonic reactions, drowsiness, dry mouth, blurred vision, urinary retention, hypotension (low blood pressure), allergic reactions, occasional jaundice.

Metoclopramide - acute dystonic reactions, facial and muscle spasms, drowsiness, restlessness, diarrhoea, depression

Domperidone - acute dystonic reactions

SSRAs (Ondansetron, gransisetron) - constipation, headache, altered liver function.

The main beneficial effects reported from use of cannabinoids are a reduction in the incidence and severity of nausea and vomiting (emesis), and stimulation of appetite, together reducing the severity of cachexia - wasting syndrome - in patients receiving chemotherapy treatment.

Clinical Trials involving THC

Sallan et al (1975) found 10mg THC "significantly more effective" than placebo at reducing nausea and vomiting in 22 chemotherapy patients. Chang et al (1979) found 10mg oral or 17mg smoked THC to decrease methotrexate-induced nausea and vomiting compared to placebo in 14 of 15 patients. Frytak et al found 15mg THC better than placebo at inhibiting prochorperazine-induced emesis, but noted some of the 116 gastrointestinal cancer patients to find the side effects (sedation, "high" dysphoria, hypotension & tachycardia) intolerable. Orr & McKearnan found 7mg THC to be more effective than prochlorperazine and placebo in 55 patients, of which 82% reported a high. Lucas & Laszlo found 15mg or 2x5mg THC more effective than placebo or standard regimes.

However Chang et al found 3-hourly oral (10mg) or smoked (17.4mg) THC ineffective compared with placebo in a small study of 8 patients receiving adriamycin and cyclophosphamide. Niedhart et al compared THC and Haloperidol in 52 chemotherapy patients finding no difference in efficacy between the two drugs. Gralla et al found 10mg THC more effective than placebo, but less effective than metoclopramide in controlling cisplatin-induced vomiting in a 27-patient study. Ungerleider et al in a large study of 214 patients, found 4-hourly 7.5-12.5mg THC and 10mg prochlorperazine equally effective in reducing nausea and vomiting, but noted THC was preferred by more patients. Lane et al found significant improvement both with THC (10mg dronabinol) and prochlorperazine, and the combination more effective than either alone in abolishing nausea and vomiting in 62 patients.

Clinical Trials involving Nabilone

Nagy et al studied 47 patients receiving cisplatin, finding nabilone more effective than prochlorperazine or placebo in reducing nausea & vomiting caused by cisplatin. Herman et al found similar results with 113 patients receiving cisplatin, cyclophosphamide & mustine therapy. Einhorn et al studied 100 chemotherapy patients, finding nabilone significantly more effective than prochlorperazine and preferred by 75% of patients, but noted lethargy and hypotension, similar results found in studies of 114 patients by Wada et al, in 36 patients by Levitt et al, 18 patients by Johannson et al, 26 patients by Ahmedzal et al and 24 patients by Niranan & Mattison.

Jones et al found "significant reduction in nausea and vomiting with nabilone compared to placebo" in a study of 54 patients and noted acceptable side effects to include dizziness (65%) and drowsiness (51%). Niederle et al found nabilone significantly better than alizapride in reducing cisplatin-induced nausea & vomiting in 20 patients. Pomeroy et al found nabilone superior to domperidone in reducing vomiting episodes among 38 patients, as did Dalzell et al in a study of 23 children, finding that despite more side effects it was preferred by two thirds of respondents, and a study of 30 children by Chan et al found nabilone superior to prochlorperazine.

Studies involving natural cannabis

Vinciguerra et al studied 56 cancer patients unresponsive to conventional antiemetic agents, who were asked to rate the effectiveness of marijuana compared to prior chemotherapy cycles. Smoked marijuana was rated as "moderately effective" or "highly effective." by 78% of patients. The authors concluded that marijuana had antiemetic efficacy, but no control group was used and the patient population varied with respect to prior marijuana use or THC therapy.

A double-blind, cross-over, placebo-controlled study by Levitt et al compared smoked marijuana with oral THC among 20 patients receiving a variety of chemotherapy drugs. The efficacy was similar, with 25% of patients achieving complete control over vomiting. Seven patients (35%) indicated apreference for oral THC over marijuana; 4 patients (20%) preferred smoked marijuana and 9 patients (45%) expressed no preference.

Neither study investigated the time course of antiemetic control, advantages of self-titration with the smoked marijuana, or ability of patients to swallow the pills. Patients with severe vomiting are unlikely to be able to swallow or keep pills down long enough for them to take effect. The onset of drug effect is much faster with smoked THC in cannabis than it is for oral delivery, and the differences in cannabinoid content of smoked cannabis compared to the oral THC route can alter the users perceptions and subjective effects. Haney et al reported smoked cannabis to make users feel "mellow" whereas oral THC did not. . Although many cannabis users claim that smoking the drug provides more effective relief from vomiting than oral THC, no controlled studies have yet been published which firmly establish this to be the case.

Conclusions of Major Recent Inquiries

The British Medical Association concluded: "Cannabinoids are undoubtedly effective as anti-emetic agents in vomiting induced by anti-cancer drugs" and that "Systematic trials of the effectiveness of cannabinoids in combatting vomiting resulting from different chemotherapy agents should be carried out".

The United States Institute of Medicine report concluded:

"In patients already experiencing severe nausea or vomiting, pills are generally ineffective, because of the difficulty in swallowing or keeping a pill down, and slow onset of the drug effect. Thus an inhalation (but, preferably not smoking) cannabinoid drug delivery system would be advantageous for treating chemotherapy-induced nausea." ... "It is possible that the harmful effects of smoking marijuana for a limited period of time might be outweighed by the antiemetic benefits of marijuana, at least for, patients for whom standard antiemetic therapy is ineffective and who suffer from debilitating emesis. Such patients should be evaluated on a case by case basis"

The House of Lords Science & Technology Select Committee made the following findings and recommendations:

"...cannabis and cannabinoids are likely to be of benefit as anti-emetics only to the small proportion of patients who do not respond to existing treatments, or possibly in the treatment of the delayed stages of emesis which can occur for some days following cancer chemotherapy, and which do not respond well to the serotonin antagonists. Nevertheless, cannabinoids are undoubtedly effective as anti·emetics and more research in this field might explore their use in combination with the serotonin antagonists, help to determine for which patients they are most appropriate, and examine the potential of the allegedly less psychoactive cannabinoid D8·THC, for which there have been encouraging preliminary clinical results"

"Unlike cannabis itself, the cannabinoid THC (dronabinol) and its analogue nabilone are already accepted by the Government as having medical value -- producing the anomaly that, while cannabis itself is banned as a psychoactive drug, THC, the principal substance which makes it psychoactive, is in legitimate medical use. Some of our witnesses are prepared to contemplate wider medical use of the cannabinoids, but not of cannabis itself. We disagree, since some users of both find cannabis itself more effective. We do, however, welcome the inclusion of THC in the trials proposed by the Asscher group, in like-for-like comparison with cannabis itself"

"Dronabinol (THC), though not licensed in this country, has already been moved to Schedule 2 to the Misuse of Drugs Regulations, and nabilone is a licensed medicine and not a controlled drug; so no Government action is required in either case to permit clinical trials or indeed prescription. ...we recommend that the Government should raise the matter of rescheduling the remaining cannabinoids with the WHO in due course, in order to facilitate research."

"Our principal reason for recommending that the law be changed, to make legal the use of cannabis for medical purposes, is compassionate. Illegal medical use of cannabis is quite widespread; it is sometimes connived at and even in some cases encouraged by health professionals; and yet at present it exposes patients and in some cases their carers to all the distress of criminal proceedings, with the possibility of serious penalties. We acknowledge that, if our recommendation were implemented, the United Kingdom would be moving out of step with many other countries; we consider that the Government should not be afraid to give a lead in this matter in a responsible way."

Summary

Levitt in an early review presentation, suggested:"The use of cannabinoids as cancer chemotherapy anti-emetics represents, in essence, the use of a drug with a relatively undefined mechanism of action to treat the side effects of other drugs, also with relatively undefined mechanisms of action, which are being used to treat cancer, a disease or series of diseases the precise nature of which remains enigmatic." Since Levitt's review, there have been major advances in cannabinoid pharmacology and in understanding of the cancer disease process. In particular, research by Herkenham et al demonstrated the presence of numerous cannabinoid receptors in the nucleus of the solitary tract, a brain center that is important in the control of vomiting.

Although other recently developed anti-emetics are as effective or more effective than oral THC, nabilone or smoked cannabis, for certain individuals unresponsive to conventional anti-emetic drugs, the use of smoked cannabis can provide relief more effectively than oral preparations which may be difficult to swallow or be expelled in vomit before having a chance to take effect. The psychoactive/euphoriant effects of THC or smoked cannabis may provide an improvement in mood, whereas several conventional preparations e.g. phenothiazines such as haloperidol (known as "major tranquillisers" and also used in the treatment of psychoses such as schizophrenia), may produce unwanted side effects such as excessive sedation, flattening of mood, and/or distressing physical "extrapyramidal" symptoms such as uncontrolled or compulsive movements.

In the USA, synthetic THC (Dronabinol) is available for use as an adjunct to cancer chemotherapy treatment, and in the UK, both the British Medical Association and House of Lords recognised the potential for use of cannabinoids in preventing nausea and vomiting.

References

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