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Medicinal Cannabis in Oncology Practice: Still a Bridge Too Far?

Department of Medical Oncology, Erasmus MC University Medical Center Rotterdam—Daniel den Hoed Cancer Center, Rotterdam
Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands
Erasmus MC University Medical Center Rotterdam—Daniel den Hoed Cancer Center, Rotterdam and Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, MD

In the 1980s and 1990s, most of the interest in cannabis (marijuana, hashish) focused solely on how to restrict its recreational use. However, in some specific areas of medicine, we have now entered an era in which the focus of attention has increasingly shifted to the clinical and controlled use of medicinal cannabis. Evidence with regards to the claimed benefits of medicinal cannabis is largely based on anecdotal case reports, arising from those situations in which physicians or patients themselves resorted to (prescribed) cannabis because conventional therapy was inadequate or was not effective. Several patient representative groups (especially for patients with cancer, multiple sclerosis, and AIDS) claim favorable effects of medicinal cannabis and advocate its use. However, it remains unclear to what extent therapeutic effects can be attributed to definable, physiological, that is objective, effects or to the benefit of psychomimetic or psychological effects. In the Netherlands, a national agency on medicinal cannabis (the Office of Medicinal Cannabis, The Hague, the Netherlands) has been established by the Dutch government following an ongoing public debate, involving diverse social and medical-oriented areas, combined with the growing need and wish to initiate well-designed clinical trials with cannabis. In the past, Dutch patients were forced to frequent illegal coffee shops for their supply of medicinal cannabis, or even to produce cannabis themselves at home. Since September 2003, under the responsibility of the Office of Medicinal Cannabis, the production and distribution of a legal, standardized cannabis product for medical treatment purposes has become a reality. This office claims that for the following indications a reasonable chance of effect can be expected of medicinal cannabis: spasticity with pain (for instance in multiple sclerosis and spinal cord injury), nausea and vomiting (chemotherapy, radiotherapy, and HIV-medication related), chronic neuralgic pain, Gilles de la Tourette syndrome, and palliative treatment of cancer and HIV/AIDS.¹ In this commentary, we will discuss the position of (medicinal) cannabis in oncology practice, viewed from the Dutch experience.

Pharmacology of Cannabis
To date, the majority of clinical research has been conducted with isolated cannabinoids, that is, pharmaceutical extracts of Cannabis sativa L or synthetically derived single compounds which act on the cannabinoid receptors CB₁ and CB₂.² In this commentary, we will refer to medicinal cannabis as an integral total product prepared from the cannabis plant, such as marijuana. As experience has been gathered predominantly with the main cannabinoid 9-tetrahydrocannabinol (THC), relevant data on synthetically derived cannabinoids will be discussed as well. THC is synthetically produced and commercially available as dronabinol (Marinol; Solvay Pharmaceuticals Inc, Marietta, GA), and is formulated as capsules for oral administration.³ Clinical studies using marijuana have also been conducted, particularly in palliative treatment of HIV/AIDS.

With the introduction of legal medicinal grade cannabis in the Netherlands, a well-defined product with a known and constant THC content that meets pharmaceutical quality standards is now available by prescription to Dutch patients. Indeed, the standardized production process greatly reduces the large degree of variability in THC content, and that of two other main cannabinoids, cannabinol (CBN) and cannabidiol (CBD). Until now, two cannabis varieties have been available for medicinal purpose, one of which contains approximately 18% THC and 0.8% CBD, the other of which contains 11.5% THC.¹ Currently, the degree of variability in content uniformity is below 15%,¹ which is low for herbal products (phytoproducts), and only marginally exceeds the specifications (variability < 10%) that apply to licensed drugs. Nonetheless, the recommended routes of administration (inhalation by smoking or vaporization, or oral intake as tea) introduce a large degree of variability in an individual's exposure to THC and other cannabis constituents.² In addition addition, when cannabis is smoked or inhaled in a joint, waterpipe, or vaporizer, THC concentrations in the blood rise and decline rapidly. Peak concentrations and its coupled psychomimetic effects are seen within minutes, and after an hour levels are decreased to less than 10%. When cannabis is taken orally, for instance as tea, bioavailability is lower, and maximum levels and the psychomimetic effects are seen after 1 to 2 hours.²

Given the chance that the psychomimetic adverse effects and impaired psychomotoric effects of cannabis can negatively influence the performance of daily tasks,^2,4 it is necessary for its effects to be predicted with a certain degree of accuracy if one wishes to prescribe medicinal cannabis on a regular basis as an equivalent alternative to other drugs. More than 60 cannabinoids have been reported to be present in cannabis, albeit in varying amounts.² The degree to which extent their pharmacologic actions are known varies largely. In addition, due to the fact that these substances have diverse pharmacologic effects, predicting the overall pharmacologic effects of medicinal cannabis is difficult, and furthermore complicated by the nature of an individual's disease.

Indications and Adverse Effects
Up until now, the majority of clinical experience has been gathered with synthetically produced THC, in most cases administered for antiemetic purposes.^5,6 In a randomized clinical trial, dronabinol in combination with prochlorperazine showed significant additive or synergistic effects.⁷ The antiemetic effect of cannabinoids is largely mediated by CB₁-receptors in the brain and the intestinal tract, though for a part their effect may be receptor-independent as well.^5,8 Following the introduction of potent antiemetic 5HT₃-antagonists, interest in THC has decreased in oncology. However, delayed nausea and emesis, which is a multifactorial problem and may be triggered by other neurotransmitters than serotonin, remains a problem for which medicinal cannabis might be a therapeutic option.^9,10 As nausea and vomiting impose serious discomfort during cancer treatment, more research on the position of medicinal cannabis seems justified.

According to some reports, patients seemed to prefer cannabis products more than conventional antiemetic regimens.⁶ However, it is not clear whether the claimed preference is due to the antiemetic effects of cannabis or due to certain psychomimetic side effects, such as euphoria, relaxation, and drowsiness. Contrary to these psychomimetic effects of medicinal cannabis and dronabinol, dysphoria and depression are reported less frequent.¹¹ Effects on the CNS, such as disturbances in perception, memory, reaction time, and coordination are seen occasionally as well.^2,12 In contrast to its immunologic effects, which are mainly mediated by the CB₂-receptor, the psychomimetic and peripheral effects are mainly mediated by the CB₁-receptor.² Indeed, some cancer patients who use medicinal cannabis for palliative purposes, report a better mood and quality of life as a result of its psychomimetic effects.⁵ However, patients may develop tolerance to some of these effects, and to our knowledge, randomized controlled clinical trials designed to compare the effects of psychological counseling in combination with conventional drug therapy to the effects of short-term medicinal cannabis are lacking.

Recreational users of cannabis report increased appetite and often do eat more, but through which pathway this process is mediated is not exactly known.¹³ As is also the case for patients with cancer, weight loss and anorexia is a problem often seen in patients suffering from HIV infection. It has been suggested that in a subset of HIV patients, THC can play a role in stabilizing the weight loss associated with the AIDS-related wasting syndrome.¹⁴ However, a study comparing the synthetic progesterone megestrol with cannabinoids, showed no additional effect to megestrol on appetite and weight gain.¹⁵ Although effectiveness of THC and medicinal cannabis has been claimed for appetite- and cancer-related anorexia by anecdotal case reports and several studies,^5,16 a working group of the French National Federation of Cancer Centres recently classified THC for this indication as a compound belonging to a group of substances of which the methodology of the available studies is weak and/or of which the results of the performed studies are inconsistent.¹⁷ This expert panel recommended that such drugs should not be used outside clinical trials, or only for incurable diseases. Clearly, at the moment, in oncology practice, there is no role upfront for medicinal cannabis in the treatment of disease or chemotherapy-induced anorexia.

Medicinal effects of cannabinoids have also been observed in disease syndromes associated with spasticity and neuropathic pain, though consistent evidence that cannabinoids are effective is still lacking.^18,19 A limited number of small randomized, placebo-controlled studies in which oral cannabinoids like dronabinol were administered to patients suffering from cancer-related pain have been published.^20,21 Indeed, compared to placebo, most of these studies showed analgesic effects of synthetic cannabinoids. However, as a systematic literature review concludes, single cannabinoids, especially THC, are at best equally effective in reducing pain in cancer patients as the opioid codeine,²² which might be explained by the fact that the CB₁-mediated pathway partly overlaps the pathway stimulated by opioids.²³ To lower the incidence of opioid-induced adverse effects, such as delirium, and tolerance to opioids in the future, medicinal cannabis combined with opioids may gain a place in the adequate treatment of cancer-related pain of neuropathic origin.^23,24 However, as medicinal cannabis and cannabinoids may play a role in the onset of delirium as well,²⁵ caution is required.

It is generally assumed that cannabinoids have a wide therapeutic index, and as such, the risk of the occurrence of acute serious intrinsic adverse effects is low, and within the range of risks associated with many other medications. However, serious cardiovascular effects cannot be excluded altogether, which may carry a risk for patients with unknown pre-existing cardiovascular disease.^12,26 Indeed, in a few cases, occasional cannabis use has been associated with sudden and unexpected death due to an acute cardiovascular event.^26,27 One of the well-known acute effects of cannabis is an increase in heart rate, and it also leads sometimes to an increase in blood pressure.²⁸ Tolerance to sympathicomimetically induced tachycardia usually develops quickly, within 2 weeks.²⁹ If any pre-existing disease impairs heart muscle function or prevents delivery of increased oxygen supply to the heart muscle or the brains, concomitant use of medicinal cannabis could have serious effects.³⁰ Certain drugs, such as tricyclic antidepressants, sympathomimetic agents like amphetamine and cocaine, and anticholinergic drugs like atropine and antihistamines, may predispose to tachycardia and cardiac arrhythmias. Combining such drugs with medicinal cannabis may therefore provoke cardiovascular complications as well,³ though we are not aware of any report describing a lethal outcome that was solely related to the acute toxicity of medicinal cannabis.³¹

Cannabis and Cancer
It is known that after smoking cannabis, inflammation and precancerous signs can be observed, attributable to high concentrations of cannabinoids, which are structurally related to the carcinogenic cyclic aromatic hydrocarbons present in inhaled tar after cigarette smoking.^32-34 Studies suggest that inhaled THC is capable of activating transcription of CYP1A1 in the lungs, and of simultaneously inhibiting its function competitively, which implicates that smoking medical cannabis may impose a risk for developing smoking-related cancers.³² Although probably of limited importance in the treatment of patients with advanced cancer who will use medicinal cannabis generally in a tea formula for a limited period of time, epidemiologic studies found evidence for higher incidence of cancer in recreational cannabis users, of which one found a relation with frequency and duration of smoking cannabis.^35,36 However, other studies do not show such relations.^37,38 Currently, the relationships between cancer and medicinal oral use of cannabinoids, and cancer and medicinal cannabis as tea are not known. Despite relations between higher incidence of certain types of cancer, such as glioma, airway, and prostate cancer, and cannabis exposure,^35,36,39 the question has been raised whether cannabinoids and their derivatives could be used to develop new anticancer therapies themselves.⁴⁰ Indeed, certain cannabis components, like CBD and THC, have antitumor properties in different cell lines and in mouse models.^40,41 However, caution is needed in clinical use of medicinal cannabis in oncology practice, because recently it has been shown that THC and other cannabinoids are capable of inducing cancer cell proliferation in certain tumor cell lines.⁴²

Drug Interactions
Because of the broad spectrum of cannabinoids present in cannabis, the potential for pharmacodynamic and/or pharmacokinetic interactions with other drugs, the outcome of which can be two sided (inhibitory or inducing), cannot be excluded. Combining medicinal cannabis with barbiturates, benzodiazepines, opioids, antihistaminica, muscle relaxants, ethanol, or other CNS depressants, may lead to excessive central nervous depression.³ Use of THC is reported to increase half life of concomitant barbiturates and antipyrine, whereas discontinuation is said to increase the metabolic clearance of pentobarbital.⁴³ Furthermore, smoking cannabis may increase theophylline metabolism, leading to less effectiveness of this drug.⁴⁴ To what extent CBD, which might have greater effects on drug metabolism than THC, influences the effects of THC on the pharmacokinetic profile of other drugs remains to be investigated.⁴³ It has also been reported that cannabinoids can influence each other's pharmacokinetic profile.² For instance, CBD modulates the extent to which the psychoactive THC-metabolite 11-hydroxy-9-tetrahydrocannabinol (11-OH-THC) is formed due to inhibition of the cytochrome P450-enzyme system (CYP). Finally, it has been suggested that THC, THC-metabolites, and CBD induce certain CYP isoforms on prolonged exposure.²

One case report describes a fatal combination of sildenafil (Viagra; Pfizer, New York, NY) and recreational use of cannabis, which was attributed to increased sildenafil plasma levels due to an inhibitory effect of cannabis at the level of CYP3A4.⁴⁵ Indeed, undesirable interactions between concomitantly administered drugs and/or herbal products and cytotoxic chemotherapeutic drugs metabolized by CYP-isozymes, especially CYP3A, are a major risk in oncology and should not be neglected. The potential inducing or inhibitory effects of medicinal cannabis with regard to CYPs are as yet poorly documented, and therefore any use of medicinal cannabis in oncology patients should be restricted. If concomitant administration of medicinal cannabis is deemed necessary, in our view, treatment with certain chemotherapeutic drugs that are sensitive to altered CYP3A function, such as topoisomerase I inhibitors like irinotecan, taxanes like docetaxel, and imatinib, should be undertaken under pharmacokinetic surveillance only, and dose adjustments should be considered in subsequent courses if required.

The Dutch Experience
According to a survey of 400 physicians, both general practitioners and specialists in the Netherlands, which was performed just before the legal introduction of medicinal cannabis, only 6% said that they were under no condition willing to prescribe medicinal cannabis, while 60% to 70% regarded medicinal cannabis sufficiently socially accepted and would prescribe it if asked for by a patient.⁴⁶ Fifteen percent of questioned clinicians indicated that they thought that medicinal cannabis was a dangerous drug. Striking was the finding that about 60% of the responders indicated that they did not feel sure about their knowledge on medicinal cannabis and wanted to be informed more specifically on indications, possible adverse effects, and dosing routes and frequency. After its legalization in Canada, local physicians have been reluctant to prescribe medicinal cannabis for the same reasons.⁴⁷ Although, as the mentioned survey indicates,⁴⁶ the introduction of medicinal cannabis and its use by patients is not supported by a small percentage of health care professionals in the Netherlands, Dutch oncologists and other clinicians can now offer their patients a legal prescription for medicinal cannabis, which patients can obtain at their local pharmacy. In addition to the Netherlands and Canada, a number of other countries is also planning to make the product legally available for medicinal purposes, whereas in others these steps and the experiences in the Netherlands are followed with great skepticism.⁴⁷ In the United States, cannabis is still classified as a drug that has no medicinal use, and furthermore, the incidence of illegal, nonmedicinal use is high. However, 1.5 years after its introduction, initial worries among a part of the Dutch population that medicinal cannabis prescription would exceed the expected use based on estimations of former illegal use for medical purposes, or that medicinal cannabis itself would find its way to the black market for recreational use, are unjustified. The fact that the controlled production and distribution makes it more expensive may be part of the explanation for this, though the patient's health insurance may be willing to pay for it. In addition, on the tolerated "black market," marijuana varieties with higher THC content are available,⁴⁸ and some patients prefer these varieties claiming that they experience sufficient effect from the legal medicinal cannabis. Because the use of legal medicinal cannabis has not met the expectations, its legalized distribution by the Office of Medicinal Cannabis is still a loss-making business.

Relatively little information on the group of cancer patients using medicinal cannabis is available, partly because medicinal cannabis use was for a long time illegal, and also because the patient group is very heterogeneous. Recently, a survey performed on 200 patients who were using medicinal cannabis during the first months after its introduction in the Netherlands was published.⁴⁹ The survey showed that most of the respondents had previous experiences with cannabis use for medicinal purposes or with synthetic cannabinoids such as dronabinol, whereas a minority of 40% were "new" users. Most patients were satisfied using medicinal cannabis; only 10% of patients reported moderate to more severe transitory adverse effects. In about half of the users, the patients themselves took the initiative to suggest medicinal cannabis to their treating physicians as a therapeutic option, whereas in about 30% of users the initiative was taken by the involved general practitioner or medical specialist. In the remaining 20% of users, it was a joint initiative of both patient and clinician. Seventy-five percent of respondents used their medical cannabis in the form of tea, mostly one to four times a day.

Among the medicinal cannabis users, only 8% of them were cancer patients, whereas the majority of patients (42%) suffered from multiple sclerosis. The most frequently reported symptoms for prescription were chronic pain and muscle cramps/stiffness. Other symptoms for prescription included postural/balance complaints, sleeplessness, and fatigue. Two-thirds of the patients described their complaints as serious, and 30% as moderate. As 90% of respondents used concomitant medication, a host of different comedications was found. However, a tentative indication for subjective or objective effect is the finding that 40% of patients indicated that after starting medicinal cannabis they had been able to decrease the use of other medication. Analgesics (reported by 37% of patients), opioids (27% of patients), antiflogistics (27% of patients), and antiepileptics (18% of patients) were reported as the most common comedication. Two of the 16 questioned patients who suffered from cancer, were reported to use chemotherapeutics at the same time.

Conclusion
In this era of evidence-based medicine and obligatory reduction of costs in health care, the introduction of a new drug should only be accepted after the substance has proved to be a rational, relatively safe, and useful additive to the current medicinal arsenal. With the introduction of legal medicinal cannabis in the Netherlands, the availability of a standardized, controlled product of pharmaceutical quality has now opened doors to perform clinical studies to investigate its claimed effectiveness and its potential to interfere with the pharmacodynamic and pharmacokinetic profiles of anticancer drugs. To date, it remains to be determined if medicinal cannabis has an additive value in oncology practice as compared with the currently available conventional drugs and/or to isolated synthetic cannabinoids. Well-designed clinical trials that undisputedly prove the advantages of medicinal cannabis are lacking, and it is far from clear for what indications medicinal cannabis may be a justified treatment option. Furthermore, additional research is required to determine the optimal administration route and dosing regimen, because gaps in our knowledge on these fundamental questions exist as well. For example, studies are needed to define whether orally administered, smoked, or vaporized medicinal cannabis relieves delayed chemotherapy-induced nausea and vomiting, or improves cancer-related weight loss and anorexia, and which dose should be recommended for which patient. As mentioned previously, issues related to safety need to be resolved urgently as well. Clinical studies evaluating the potential for pharmacokinetic interactions between medicinal cannabis and chemotherapeutic agents metabolized by CYP3A are ongoing. At this time, development of cannabis and isolated synthetic cannabinoids for medicinal purposes is still in its infancy and has a long way to go. Until consistent results of well-designed clinical trials become available, in our view, regular prescription of medicinal cannabis in oncology practice is a bridge too far. Currently, its use should be restricted to patients participating in clinical trials, and to patients for whom no other effective therapy is available and who are not treated with an anticancer drug whose pharmacokinetic profile may be unpredictably influenced by medicinal cannabis.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

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