Cannabis and Cancer Care
Growing popularity of alternative medicine and cannabis has raised numerous questions regarding the potential of cannabis use beyond palliative and symptomatic treatment in cancer care. Due to increasing interest in the natural benefits of cannabis, in an era of legalized cannabis and readily accessible mainstream media, inaccurate claims regarding cannabis and its role in the treatment of cancer have become rampant [46, 87]. In effort to prevent patients from foregoing conventional cancer therapy as a result of this misinformation, it is the responsibility of the medical community to ensure that these patients are well informed to avoid consequences including avoidable deaths.
Laboratory Studies
THC exerts a variety of biological effects by mimicking endogenous substances, including the endocannabinoids anandamide and 2-arachidonylglyercol (2-AG) that of which bind and activate specific cannabinoid receptors. Thus far, there have been two G protein coupled, cannabinoid-specific receptors that have been cloned and characterized from animal studies in the form of CB1 and CB2. CB1 receptor is predominantly found in the central nervous system with a minority in the peripheral nervous system and various extraneural sites (including vascular endothelium, spleen, eye, and testis) [34]. The CB2 receptor is primarily expressed in the immune system at the cellular and tissue level of lymphocytes to lymph nodes, respectively [34]. An exciting area of research includes the applicability of these two receptors as potential targets for anticancer agents.
Mechanisms of cannabinoid antitumor action are still unclear and inconsistent; however, the current leading proposals include the induction of apoptosis [29, 31, 83], cell cycle arrest [20, 62, 63], and the inhibition of angiogenesis and metastasis [8, 14, 76].
Additionally, it has been proposed that cannabinoids have utility as adjuvant therapies for cancer treatment, but the true usefulness still remains unclear. Thus far only two studies have been carried out involving gamma radiation and tamoxifen.
Although the large majority of studies pertaining to cannabinoid use in cancer have been for their palliative effects, the utility of cannabinoids as anticancer therapies still has room to develop. As stated, there have been proposed mechanisms of how cannabinoids may have antitumorigenic potential in culture and animal models; however, these have not successfully translated to in vivo studies as they have been disappointingly ineffective and/or toxic when tested.
Clinical Studies
To date, there are no active clinical trials involving the use of cannabis or its derivatives in the treatment of cancer. The only trial that has been published includes a phase 1 cohort of nine terminal patients with known recurrent glioblastoma, involving the use if intratumoral injection of delta-9-THC that demonstrated no significant clinical benefit with fair safety profile [35, 95].
Several trials have previously been reported to be completed without any finalized published data. These trials included a phase 2 pilot study of 21 participants with recurrent glioblastoma multiforme involving the use of nabiximol alongside temozolomide compared to a placebo arm of temozolomide. A report by GW Pharmaceuticals reported an 83% 1-year survival compared to the 53% in the placebo arm (p = 0.042) [85], prompting a flurry of media including one politician and his family to use this as a platform for the legalization of cannabis for treatment of cancer. Another trial including 60 solid tumor cancer patients used oral CBD as a single salvage treatment without any published results at this time (NCT 02255292).
In a phase II trial, Yeshurun et al. demonstrated the potential immunosuppressive and anti-inflammatory effects CBD may have as prophylactic treatment for patients undergoing stem cell transplantation. In their study, they had 48 participants with acute leukemia or myelodysplastic syndrome received CBD 300 mg/day alongside their conventional prophylaxis treatment. After comparing these patients from 101 historical controls, they demonstrated a lower incidence of grade 2 to grade 4 graft versus host disease, necessitating the need for randomize control studies [101].
In so far as the pediatric population, there are no clinical trials to date for the use of cannabis as treatment for cancer. Published reports thus far in this population have been limited to case reports suggesting cannabis as a promising anticancer treatment [27, 88].
Cannabis and Symptom Management in Cancer Care
Cannabis has been long used as an avenue for pain relief [82] and often perceived by clinicians with negative connotation due to their association with illegal substances [10], often excluding individuals from candidacy from traditional (albeit limited) pain relief in the form of opiates. Medical cannabis refers to the use of cannabis or cannabinoids (derivatives of the former) as medical therapy to treat and alleviate symptoms. Beyond these notions, cannabis is commonly used by cancer patients during therapy, frequently without the oncologist’s knowledge [16]. This poses increasing concern due the influence of cannabis, cancer therapy, and cancer.
In a study that allowed 17,000 patients to enroll for the use of cannabis for cancer symptoms, the most common causes for use of cannabis were pain, well-being, appetite, and nausea [97]. Surprisingly, only 42% listed their oncologist as providing information regarding the use of cannabis to address their symptoms. To further elaborate on prescription practices and the attitudes of the physician regarding the use of cannabinoids as part of their management, a survey involving 166 physicians from a region of Canada found that cannabinoid prescription was at a rate of only 27% (for any indication). Among those who prescribed cannabinoids did so for fewer or equal to five patients in the last year, which was explained due in large part from lack of comfort with prescription of cannabinoids. Factors of improving degree of comfort included need for guidance and education including guidelines (i.e., dosing) and need for robust evidence. Limitations to this report included prescribing practice for only cannabinoids and not medical marijuana added, concern that the reported prescription rate was an overestimate as nonresponders may have not decided to complete the survey because they did not prescribe or were not comfortable with prescribing cannabinoids. The authors and the surveys conducted concluded that guidelines and education were needed [91].
A cross-sectional survey of 937 cancer patients conducted at a cancer center in the state of Washington (where medical and recreational use of cannabis is legalized) included 24% reported regular cannabis users. Additionally, reported non-mutually exclusive reasons for cannabis use among these patients were physical symptoms (75%), neuropsychiatric symptoms, recreational use/enjoyment, and treatment of cancer. Among the physical symptoms that were reported included pain, nausea, and loss of appetite. Interestingly, the majority of patients preferred to obtain information regarding cannabis from their care team, but less than 15% of patients reported receiving information from their cancer physician or nurse [71].
Cancer Pain
Animal Studies
Although proposals in the effectiveness of cannabinoids in cancer pain has often been discussed since the 1970s, it was not until the mode of action was further elucidated by peripheral action and at both CB1 and CB2 receptors [12, 23, 33, 84] that cannabinoids had affirmed an avenue for analgesia in multiple types of cancer pain.
Primary treatment for cancer pain has previously surrounded the use of opioids; however, due to ineffective relief, side effects, as well as the development of tolerance, there are increasing popularity of patients switching from opiate use to cannabinoid use.
Cannabinoids have demonstrated ability to potentiate analgesic effects of morphine [4] and curtail the incidence of tolerance [15]. Analgesia has been achieved through the activation of the two cannabinoid receptor types (CB1 and CB2). While CB1 is localized to the spinal dorsal horn, periaqueductal grey, and dorsal root ganglia, the CB2 receptors are found in immune cells and keratinocytes [96].
In a model involving the inoculation of osteolytic cells into the humerus of mice, a nonselective CB1/CB2 agonist (WIN55,212) was intraperitoneally administered, effectively creating time and dose-related systemic antihyperalgesia [47]. Given the known side effect of loss of coordination and catalepsy in the induction of CB1 receptors, this effect was confirmed secondary to behavior via the cannabinoid receptor rather than the former. In a fibrosarcoma mouse model, the CB1 receptor was isolated and identified as having antihyperalgesic effect through the following use of various combinations of nonselective agonists (CP 55,940), selective antagonists (SR 141716A), and a selective CB2 antagonist (SR 144528) [37].
To address the role of peripheral cannabinoid receptors in carcinoma pain, Guerrero examined allodynia in an oral squamous cell cancer mouse model with intratumor administration of WIN55,212 or selective CB2 agonist (AM1241) attenuated mechanical hyperalgesia without any temporal association to a tumor growth effect. Interestingly, Guerrero also demonstrated increased CB1 receptor expression in the dorsal root ganglia ipsilateral to the inflicting cancer.
The disparity seen between this model and the previous fibrosarcoma model may have been from different profiles emanating from their respective primary cancers as well as well as the route of cannabinoid administration (local vs systemic).
In three separate studies involving the implementation of vincristine, cisplatin, and paclitaxel, cannabinoids were demonstrated to be effective in relieving the induced chemotherapy-induced peripheral neuropathy (CIPN). These studies demonstrated that spinal sites of action were implicated both CB1 and CB2; receptor-mediated processes were involved in the suppression of CIPN [48–50, 78, 98].
Human Studies
Cancer pain is secondary to cancer-related growth of tissue or secondary to treatments implemented to address it in the form of bone, neuropathic, visceral, or somatic pain. When cancer pain is severe and persistent, this is often resistant to conventional therapy including opiates. The control of pain is a cornerstone of cancer treatment promoting enhanced quality of life, improved functioning, improved compliance, and a way for patients to have an improved outlook on life.
Oral delta-9-THC effects were measured for cancer pain in a double-blind, placebo-controlled study involving 10 patients using domains of intensity of pain and relief of pain [68]. Among various dosages, there was substantial analgesic effects with 15 and 20 mg doses of cannabinoid delta-9-THC. In a follow up study involving 36 patients with the use of 10 mg of delta-9-THC, there was comparable analgesic relief as to 60 mg doses of codeine. In this same study, 20 mg doses of delta-9-THC demonstrated analgesic equivalence to 120 mg of codeine, however was mired with intolerable side effects including somnolence, ataxia and blurred vision [68].
In a multicenter, double-blind, placebo-controlled study including 177 patients with advanced cancer with moderate-to-severe cancer-related pain over a 2-week time frame, THC:CBD nabiximols extract and THC extract were compared for their analgesic management [44]. After these patients were randomized to a THC/CBD extract, THC extract, or placebo extract group, they determined that the combination nabiximol extract was efficacious for pain relief as an adjunctive treatment for those that did not achieve an analgesic response to opioids [44]. In an open-label extension study from the previous study, involving 43 patients found that some patients continued to find relief with prolonged and long-term use of the THC/CBD oromucosal spray without need for increasing dose of spray or dose of other analgesics [45].
In a randomized, placebo-controlled, graded-dose trial involving 268 advanced cancer patients with poorly controlled pain refractory to opioid therapy, improved pain control and sleep were seen with nabiximol sprays at lower to medium doses (1–4 and 6–10 sprays/day) compared to placebo [77]. Adverse effects were demonstrated with the higher-dose group compared to placebo. This study was in contrast to one by Lichtman et al. involving 397 treatment refractory advanced cancer patients in a similar randomized, placebo-controlled setting that demonstrated nabiximol was not superior to placebo [55].
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect associated with several regularly used chemotherapeutic agents including taxanes, platinum-based agents, and vinca alkaloids. In a randomized, placebo-controlled crossover study involving 16 patients with chemotherapy-induced neuropathic pain, nabiximol was administered with no significant difference between the treatment and placebo group. In the same study, among those who responded (five patients), an average reported decrease of 2.6 points on an 11-point numerical scale was made, calling for a larger scale study [57].
A prospective observational study assessed the effectiveness of adjuvant nabilone therapy in advanced cancer patients undergoing pain and other associated symptoms (including nausea, anxiety, and depression). Following 30 days of follow-up patients who were treated with nabilone found improvement in pain, nausea, anxiety, distress, and pain compared to untreated patients. Additionally, there was an associated decreased use or greater tendency to discontinue adjuvant pain therapies including opiates, non-steroidal anti-inflammatories, tricyclic antidepressants, and gabapentin to name a few [58].
Preclinical observations that cannabis augments analgesic effects of opiates in a synergistic effect were further elaborated in a pharmacokinetic study involving 21 chronic pain patients. This study group was given vaporized cannabis in addition to either sustained release morphine or oxycodone for 5 days. The morphine arm had associated decrease in mean pain score while the oxycodone did not [4]. Several limitations including size of participant pool, duration of study, and lack of a placebo-control calls for further studies to explain the relationship of how cannabis affects the metabolism of opiates before translating these findings into regular practice.
The use of nabiximols, a combination cannabis extract comprising of THC and CBD in a 1:1 ratio is currently approved for use by Canada, New Zealand, and various countries in Europe for treatment of spasticity in multiple sclerosis. Added, Canada additionally has an indicated use of nabiximols for advanced cancer pain. Fallon et al. reported the results of two phase 3, double-blinded, randomized, placebo-controlled, multicenter trials involving the use of nabiximols in advanced cancer patients for treatment of chronic pain that were optimized on opiate therapy. On the basis of a primary endpoint using a numerical rating scale score (NRS), there was no difference in the use treatment group compared to placebo. Interestingly, a pooled analysis of these trials conducted in the United States (reported as 30% of the trial population) demonstrated improvement for nabiximols compared to the placebo in a subset of patients that were less than 65 years of age [24].
Appetite Stimulation
Animal Studies
The appetite stimulating action of the cannabis plant has largely been attributed to the effect of delta9-tetrahydrocannabinol (THC) properties. Since the 1970s THC has been demonstrated to stimulate feeding in a variety of animal models following systemic or central administrations. Studies have demonstrated the belief that endocannabinoid activity upon CB1 receptor, particularly in associated areas of the hypothalamic nuclei and nucleus accumbens, has associated effects on eating motivation and nutrition behavior. The hyperphagic actions of THC have been replicated with CB1 cannabinoid receptors, largely with agonist endocannabinoid use including anandamide and 2-arachidonoylglycerol (2-AG).
Supporting evidence for endocannabinoid involvement in appetite regulation was demonstrated in a mouse model involving CB1 receptor knockout mice (Cb1−/−) where these animals were fed either standard chow or a high-fat diet. CB1(−/−) mice did not display hyperphagia characteristic of wild-type mice (CB1+/+) and did not develop obesity. Additionally, the Cb1 knockout mice demonstrated a reduced hyperphagic response to fasting, eating less than wild-type mice.
Previous identification of two cannabinoid receptor subtypes of CB1 and CB2 receptors that are predominantly expressed in the central nervous system with some expression in gastrointestinal, adipose, and hepatic tissues, linking endocannabinoids to processes related to energy storage and metabolism that may affect appetite.
Human Studies
Appetite and weight loss are common side-effects of cancer and its associated treatments. In practice, appetite loss, involuntary weight loss, and nutritional deficiencies can be indicators of cancer severity and quality of life, physical functionality, and survival timeline.
In advanced cancer, the cause of appetite loss is believed in part to be caused by catabolism driven by pro-inflammatory cytokines, tumor products as a host reaction to tumor, and neurohormonal alterations (including hypoanabolism) [103]. Appetite loss can also have contributing secondary factors such as depression/psychosocial stress, nausea, constipation, taste alterations, or pain.
In so far as the clinical use of marijuana for appetite, significant evidence resides in the treatment of HIV wasting syndrome as advanced stages of cancer or HIV infection, and there are similar findings of progressive weight loss and loss of appetite. In placebo-controlled studies of HIV patients, smoking marijuana led to an increase in food intake which may be mediated through elevation in ghrelin and leptin as well as decreased levels of peptide tyrosine that of which regulates appetite.
Two controlled studies have demonstrated dronabinol (oral THC) that stimulates appetite and helps slow chronic weight loss in adults suffering from advanced cancers. The first was seen in a study in 1976 by Regeleson in a pool of 54 patients with advanced cancer. These patients were given dronabinol at 0.1 mg/kg three times a day. Secondly, a study by Jatoi et al. involved 469 patients with advanced cancer that had previously demonstrated weight loss. These patients were divided into treatment arms of dronabinol at a 2.5 mg BID dose, an oral megesterol at an 800 mg/day dose arm, alongside a combined treatment pool. They found that megesterol had greater efficacy over dronabinol with appetite (75% versus 11%) and weight gain (11% versus 3%), without any significant differences with the combination therapy [41].
Three additional controlled studies involving HIV-AIDS-related patients (with associated weight loss) and the use of THC (in the use of dronabinol or smoked THC) demonstrated marked, statistically significant stimulation of appetite and weight maintenance, or gain compared to placebo controls [3, 6, 92].
An additional randomized, placebo-controlled trial involving 46 cancer patients, and the use of dronabinol demonstrated improved and enhanced chemosensory perception with dronabinol use. More specifically, the dronabinol treatment arm demonstrated altered preference, appeal for foods, increased appetite, and increased intake of protein [11].
Currently, oral synthetic TCH or dronabinol is used as an appetite stimulant for the treatment of anorexia and weight loss associated with AIDS and not for advanced cancer. Dronabinol is available for use in 2.5, 5, and 10 mg capsules that can be taken up to a maximum dosage of 10 mg twice a day. Added, there are no published studies to date that have explored the effect of inhaled cannabis involving cancer patients and any impact on appetite to date.
Nausea and Vomiting Due to Chemotherapy
Development of chemotherapy treatment has been very useful in oncology practice as this has helped prolonged the lives of many patients. The use of these drugs, however, pose very difficult challenges to patients and their clinicians as they often have many associated side effects, most notably nausea and vomiting.
The emetic reflex has included vomiting, retching, and a sensation of nausea. Vomiting is a protective reflex to remove ingested toxins from the upper gastrointestinal tract. The sense of nausea serves as a warning and typically results in the cessation of ingestion and an associated aversion to repeat ingestion of the said toxin. Uniquely to cancer patients, the protective vomiting reflex does not apply as this does not remove the toxin.
Three types of emetic episodes have been described: (1) acute nausea and/or vomiting with temporal association of chemotherapy, (2) delayed nauseas and/or vomiting that proceeds after 24 hours of chemotherapy, and (3) anticipatory nausea and/or vomiting (ANV) with re-exposure to associations of the toxin [1]. ANV is potentiated with increased intensity of initial acute emetic episode. ANV has been demonstrated in at least half of patients treated, occurring in later cycles of chemotherapy.
Animal Studies
Animal models developed to assess the potential antiemetic properties of cannabinoids have been developed with the use of cats, pigeons, ferrets, least shrews, Cryptotis parva, and the house musk shrew (Suncus murinus) [70]. Rats and mice were largely excluded in these studies because they do not vomit in response to a toxin challenge [59].
The isolation of the cannabinoid receptors (CB1 and CB2) alongside the discovery of their respective endogenous ligands of anandamide and 2-aracidonoyl glycerol (2-AG) paved the way to further elucidate the findings we now have regarding the antiemetic effects of cannabinoids [25, 26].
It was in a shrew and ferret model (Van Sickle and Darmani) that the site of emesis was localized to the brainstem within the dorsal vagal complex.
The CB1 receptors have been demonstrated in the GI tract and enteric nervous system as well as in the dorsal vagal complex including the area postrema, nucleus tractus of the solitary tract, and dorsal motor nucleus in these animal models [72, 73, 93, 94], wherein cannabinoid agonists act mainly to decrease motility and act centrally to attenuate emesis.
Through various shrew models by Darmani, the endogenous cannabinoid system demonstrated a role in the both the regulation of emesis (by blocking CB1 receptors to block the antiemetic activity of cannabinoids as well as inducing emesis with higher doses of CB1 receptor antagonists) while also demonstrating a potential for promotion of emesis (with demonstration of 2-AG as a potent emetogenic agent and anandamide as a weak antiemetic) [19].
In studies involving lithium-induced emesis, THC and non-psychoactive CBD were used in shrew models demonstrating a dose-dependent suppression of lithium-induced vomiting with THC. CBD in this model produced a biphasic effect with lower doses demonstrating suppression while higher doses (20–40 mg/kg) demonstrating enhancement of lithium-induced vomiting. In these same lithium-induced vomiting models, CBD was confirmed to not act at the CB1 receptor (via reversal agent of SR-141716 that of which reversed the THC suppression but not the CBD), thereby raising further questions of alternative routes for controlling nausea and vomiting [60].
The dorsal vagal complex is densely populated with CB1 and 5HT3 receptors. In a shrew model involving combined treatment of ondansetron and Delta9-THC demonstrated complete suppression of cisplatin-induced vomiting and retching, wherein independent administrations at a similar dose was ineffective [17, 18]. Notably, the effective independent THC dose was measurably higher than the administered THC dose in the combined treatment, suggesting potential for fewer side effects at higher doses [53]. Studies have demonstrated the interaction of the cannabinoid system with the serotonergic system in the control of emesis [51].
The use of cannabis in the successful treatment of anticipatory nausea and vomiting is limited as the model of nausea was largely founded on a conditioned gaping model in rats (rats do not have a physiologic equivalent to humans as they are unable to vomit). However, the use of shrews has suggested the role of attenuating properties of cannabis through THC in re-exposure to lithium toxin models [56, 69, 70].
Human Studies
Nausea and vomiting, largely in the form of chemotherapy-induced nausea and vomiting (CINV), are the most common complaint as it is seen in up to 75% of those undergoing chemotherapy [86]. As common as these complaints arise by patients, 40% of cancer patients often fail to achieve adequate control of these symptoms [22]. The psychological impact that these symptoms convey contribute toward the development of anticipatory nausea and vomiting. Unfortunately, these symptoms contribute to reduced quality of life and feelings of helplessness and may additionally affect adherence to chemotherapy [89, 104, 105] and impaired survival as a consequence.
Several risk factors that have been identified as contributing to CINV include use of the degree of emetogenic potential of an antineoplastic therapy (i.e., platinum or anthracycline-based), previous experience of poorly controlled emesis, age, gender, history of hyperemesis gravidarum, duration of sleep the night prior to chemotherapy, anticipatory nausea/vomiting, and first cycle of chemotherapy.
Although cannabis has been used for centuries for various therapeutic applications including nausea and vomiting, cannabinoids and their antiemetic properties were investigated prior to the discovery of 5-HT3 antagonists. Nabilone (Cesamet) was the first cannabinoid agonist introduced in the 1980s for suppression of nausea and vomiting by chemotherapy [66] followed by Delta9-THC [28], dronabinol as an antiemetic and as an appetite stimulant [74].
Among all the studies conducted thus far (28 studies), the large majority of studies have surrounded the evaluation of nabilone (14) [43], with the remainder including dronabinol (3), nabiximol (1), levonantradol (4), and THC (6). Interestingly, only one clinical trial to date has compared antiemetic and anti-nausea effects of cannabinoids with 5-HT3 antagonists. All the studies included comparators that included a placebo or an alternative antiemetic agent (i.e., prochloperazine, metoclopramide, chlorpromazine, domperidone). Added, there have not been any comparative trials involving cannabinoids and aprepitant, an NK1 antagonist. Meiri et al. [61] compared dronabinol, ondansetron, or the combination for delayed chemotherapy-induced nausea and vomiting (in a double-blind placebo-controlled study) among cancer patients receiving moderate-severe emetogenic chemotherapy. The study demonstrated that dronabinol alone was comparable to ondansetron in the treatment of delayed nausea and vomiting, while the combined treatment was no more effective than either agent. This study was not designed to evaluate acute nausea and vomiting; however, the combination group did report less nausea and vomiting on the chemotherapy treatment day than placebo.
It has been noted that there is a strong preference of smoked marijuana over alternative forms of oral cannabinoids or sublingual forms. Suggested reasons for these have included ability to self-titrate smoked marijuana, ease of administration, short latency of onset for inhaled over alternatives, and the combination of action of other elements (including THC) in smoked forms. Many marijuana users have claimed that smoked marijuana is more efficacious than oral cannabinoid; however, all clinical trials thus far for the purposes of antiemesis in chemotherapy-induced nausea and vomiting have only investigated the effectiveness of oral cannabinoids (versus their counterparts of the sublingual or smoked form) largely in part due to the ability to titrate doses [36].
In the use of cannabis in the cancer population of children, it has been suggested that they may be effective in treating more difficult to control symptoms of nausea and delayed nausea and vomiting. Abrahamov et al. [2] evaluated Delta8-THC, a less psychoactive relative to Delta9-THC in children receiving chemotherapy. In their study, Abrahamov demonstrated mild irritability as a side effect and had effective acute and delayed nausea and vomiting.
In summary of the trials performed thus far, there was a suggested benefit in the use of cannabinoids but without any statistical significance. In all major national guidelines, there is no current recommendation for the use of cannabis or cannabinoid derivatives for the prevention of nausea and vomiting in this population, however, can be used as an alternative for breakthrough treatment in one guideline [7]. Added, in the pediatric guidelines due to limited evidence, there is no active recommendation for cannabinoid use [30, 99].
Chemotherapy agents have been demonstrated to stimulate the chemoreceptor trigger zone with subsequent sensory information being conveyed to the nucleus tractus solitarius and initiation of vomiting via the dorsal monitor nucleus of the vagus and the nucleus ambiguous. The dopamine (D2) receptors, histamine (H1) receptors, and muscarinic cholinergic receptors have been elucidated to be involved with regulating the process of emesis. The chemoreceptor trigger zone is initially stimulated in the area postrema in the floor of the fourth ventricle with impulses passed onto the vomiting center that includes the nucleus tractus solitarius as well as the nucleus ambiguous. Although these centers involve dopamine (D2), histamine (H1), and muscarinic receptors, antiemetic medications available vary in their ability to bind to these receptors. Anticholinergics and antihistaminergic have minimal effect on CINV. Phenothiazines, butyrophenones/butyrophenone derivatives, as well as substituted benzamides are potent dopamine receptor antagonists with varying abilities to block cytotoxic-induced emesis. Additionally, domperidone and metoclopramide’s effect on dopamine gut receptors are believed to have a dual site of action via promotion of gastric motility. Mechanism of benzodiazepines may alleviate anxiety and produce amnesia in chemotherapy-treated patients as there is no demonstration of true antiemetic activity.
Conversely, cannabinoids do not address any of these three receptors previously outlined. Nabilone has been suggested to act on opiate-type receptors in the forebrain resulting in inhibition of vomiting center via descending connections. It was proposed that associated encephalin release played a role in maintaining antiemetic center in the medulla wherein steroids similarly protect this center.
Adverse Events
Contrary to popular opinion that cannabis is a harmless pleasure, there are well-documented observed effects from an immediate to long-term basis [52]. Fatalities due to cannabis use in humans has not been substantiated since cannabinoid receptors (unlike opioid receptors) are not located in areas governing respiration. Since cannabinoid receptors are present in other tissues throughout the body beyond the central nervous system, associated symptoms of tachycardia, bronchodilation, muscle relaxation, decreased gastrointestinal motility, hypotension, and tachycardia are regularly experienced.
Cannabis is listed as a schedule 1 class drug with high potential for abuse by the drug enforcement agency. Although their addictive potential was previously lower than that of other prescription agents or substances of abuse [13, 32, 36], the rate has increased to as high as 30% [39], largely due in part from the increased availability of higher-potency cannabis [106].
Cannabinoids are stored in adipose tissue and are excreted with a half-life of 1–3 days. Abrupt discontinuation of cannabis or cannabinoid has not been seen with life-threatening withdrawal that would otherwise be seen in opiates or benzodiazepines [9].
Cannabidiol (CBD) has been demonstrated to be an inhibitor of cytochrome P450, thus concurrent therapy of antineoplastic therapy (which are often metabolized by the same enzymes) has an associated concern for potential increase in toxicity or decreased effectiveness of these therapies [42, 100].
As cannabis is commonly inhaled, questions of associated lung disease and respiratory compromise are inherent as a potential nidus for disease or exacerbation of a chronic issue. The long-term effect of low levels of marijuana exposure in a non-cancer population of 5115 patients did not make any significant impact on pulmonary function testing [75]. Smoked cannabis has also been demonstrated to contain Aspergillus, described previously in cannabis smokers undergoing renal transplant, treated for leukemia or solid tumors with AIDS, and in patients undergoing chronic steroid therapy [81]. Thus in the cancer population, a well-educated discussion of alternative routes of administration beyond smoking cannabis is important.
Cannabis use has been seen to impair driving capability in both the immediate and long-term use. Cannabis has been the most frequently associated with impaired driving-related fatalities among illicit drugs. In a meta-analysis, the risk of accident involvement increased by a factor of two following immediate use of cannabis [38]. In a culpability analysis, those who had tested positive for THC were 2.7–6.6 times as likely to be responsible for a motor vehicle accident versus those who had not been using drugs or alcohol before driving [79]. In an annual report published by a drug trafficking program in the state of Colorado (where recreational marijuana was legalized in 2012), cannabis-related traffic deaths have slowly increased from 15% to 23% between 2013 and 2018 [80].
Cannabis has well-known antiemetic properties. The emergence of cannabinoid hyperemesis syndrome (CHS) has added to the list of centrally mediated adverse effects that cannabinoids can incur that includes cyclical vomiting. Although the mechanism is unclear, several theories have included that the CB1 receptors in the enteric nervous system superseded those of the central nervous system, chronic regular use desensitizes or downregulates the antiemetic properties of cannabinoids and a disrupted Hypothalamic-pituitary-adrenal axis from upregulated ACTH secretion. Reported cases that have included CHS as potential cause of death or as a contributing factor to death have been documented [67] from complications of nonspecific electrolyte disturbances.
Interestingly, CHS is associated with a chronic excessive daily use of cannabis for at least 2 years that is often relieved by sustained cessation of cannabis use, although temporarily symptomatic relief is found with acute cannabis use. Therein creating cycle of failed attempts to maintain abstinence and unrelenting CHS with bouts of emesis. Indeed there could be some concern for ambiguity between emesis secondary to chemotherapy and CHS in patients using cannabis; however, all reported cases thus far have only included smoked cannabis [64, 90]. In addition to suggesting alternative routes of administration, ensuring that a patient has not exhausted other avenues to address their symptom care with the assistance of their treating physician is paramount (in efforts to prevent chronic habitual use).
The increasing attention of cannabis and marijuana derivatives has stimulated the rise of recreational designer drugs particularly spice/K2, which has been responsible for serious adverse effects [102], toxicity, and cases of fatalities in combination with other substances.
Future Directions
The role of cannabis and cannabinoids has potential to take on a greater role in cancer medicine as a therapeutic option for cancer-related disease and sequela of treatment. In a national survey conducted by the American Society of Clinical Oncology, 62% of cancer patients wished they had more information on the benefits and risks of medical cannabis [5]. Current government restrictions on the use of cannabis in the United States include classification as a schedule 1 drug (high potential of abuse and no accepted medical use), thereby limiting the progress of the development of drugs with cannabis components. Most major cancer societies (including the American Society of Clinical Oncology and the National Cancer Institute) [21] have declined to take position on the use of medical marijuana; however, the American Cancer Society has stated that they support the need for more scientific research on the potential risks and benefits.
By current convention, food and drugs are regulated at both the state and federal level. Without federal or state support, dispensaries are often the last line of defense for monitoring and enforcing safety of cannabis production for consumers. This should be further emphasized in a cancer population that is particularly vulnerable to infection and intoxication that seeks this avenue of treatment; this is in reference to a case of a fatal ending for a young cancer patient that had a treatable cancer and passed away from a fungal infection that stemmed from their use of contaminated medical cannabis.
Lastly, increasing changes in the social and political climate toward legalization of cannabis would allow randomized studies to address risks and benefits of cannabis while addressing measures of quality control, administration methods, and addressing optimal dosing. Added, improved regulations would allow future studies to better assess patient outcomes (i.e., disease-specific endpoints, quality of life and adverse events) using standardized measures at similar time points to insure inclusion in future meta-analysis.
Summary and Conclusion
The use of cannabis has historically been used for recreational purposes in the inhaled or vaporized format and until recently has gained traction for their potential medicinal properties. In cancer patients, there have been a total of 10 clinical trials in the use of inhaled cannabis, all of which were for chemotherapy-induced nausea and emesis. Unfortunately, the data was insufficient to provide any evidence for use of this mode of delivery. Added, there are no published controlled clinical trials for any other cancer treatment-related symptoms or cancer-related symptoms for that matter.
On the basis of cannabis derivatives, several controlled trials and meta-analyses have demonstrated support for the use of cannabinoids (dronabinol and nabilone), specifically for chemotherapy-induced nausea and vomiting. Currently, dronabinol and nabilone are approved in the United States by the FDA for only use as treatment or prevention of chemotherapy-induced nausea and vomiting. An increasing number of trials are actively evaluating the use of oral mucosal administration (in the form of a nabiximol spray) in parts of Canada, New Zealand, and other European countries.
Despite the exponential rise in cannabis use, research for a cure to cancer with cannabis has been limited to animal studies with favorable and meaningful conclusions for potential translation into human cancer research. Unfortunately research is further limited and scarce in the clinical setting as only a handful of trials have been conducted, with only one of these with published results [35].
Although many uses of cannabis and their derivatives seem potentially favorable beyond antiemesis in areas (including pain, treatment of cancer, and beyond), limitations to their analysis (specifically in the United Sates) in this context resides in barriers associated with regulation as a schedule 1 substance, finances for funding and access to research-grade product for use on a research scale [65].