Opportunities for cannabis in supportive care in cancer
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Supplemental material, Suppl-Table-1 for Opportunities for cannabis in supportive care in cancer by Amber S. Kleckner, Ian R. Kleckner, Charles S. Kamen, Mohamedtaki A. Tejani, Michelle C. Janelsins, Gary R. Morrow and Luke J. Peppone in Therapeutic Advances in Medical Oncology
Cannabis has the potential to modulate some of the most common and debilitating symptoms of cancer and its treatments, including nausea and vomiting, loss of appetite, and pain. However, the dearth of scientific evidence for the effectiveness of cannabis in treating these symptoms in patients with cancer poses a challenge to clinicians in discussing this option with their patients. A review was performed using keywords related to cannabis and important symptoms of cancer and its treatments. Literature was qualitatively reviewed from preclinical models to clinical trials in the fields of cancer, human immunodeficiency virus (HIV), multiple sclerosis, inflammatory bowel disease, post-traumatic stress disorder (PTSD), and others, to prudently inform the use of cannabis in supportive and palliative care in cancer. There is a reasonable amount of evidence to consider cannabis for nausea and vomiting, loss of appetite, and pain as a supplement to first-line treatments. There is promising evidence to treat chemotherapy-induced peripheral neuropathy, gastrointestinal distress, and sleep disorders, but the literature is thus far too limited to recommend cannabis for these symptoms. Scant, yet more controversial, evidence exists in regard to cannabis for cancer- and treatment-related cognitive impairment, anxiety, depression, and fatigue. Adverse effects of cannabis are documented but tend to be mild. Cannabis has multifaceted potential bioactive benefits that appear to outweigh its risks in many situations. Further research is required to elucidate its mechanisms of action and efficacy and to optimize cannabis preparations and doses for specific populations affected by cancer.
Cancer and cancer chemotherapy cause nausea and vomiting, pain, neuropathy, depression, sleep disorders, and other debilitating symptoms. 1 These symptoms often develop during treatment and can persist after cessation of chemotherapy, severely impacting long-term quality of life. 2 With more survivors than ever, and survivors living longer lives, 3 it is important to address these symptoms to maximize survivors’ quality of life.
Despite limited randomized clinical trials, cannabis shows promise to improve many symptoms of cancer and its treatments. 4,5 Social acceptance is also greatly increasing its use, despite lack of scientific evidence of safety and efficacy. In fact, in one community oncology clinic, 18.3% of patients with cancer reported using cannabis in 2017. 6 In a Canadian study conducted in 2017, before cannabis was legalized in that country, 18% of patients with cancer used cannabis, often to relieve cancer-related pain, nausea, or other cancer symptoms. 7 Unfortunately, although 80% of clinicians are discussing cannabis (i.e., medical marijuana) with patients, only 30% feel adequately informed to make recommendations about its use. 8 It is crucial that scientific research on cannabis be accelerated to match patient demand. Only then will clinicians and patients have reliable safety and efficacy data to inform decisions that integrate information on patient symptoms, type of cannabis, delivery system, patient preference, dose, duration, and side-effects/adverse events.
This review describes how cannabis might modulate the most common and debilitating symptoms of cancer and its treatments in the context of cancer treatment, palliative care, and survivorship. While other reviews have examined the literature on medical cannabis related to cancer care (e.g., 4,5,9 –12 ), we further explore cannabis in animal models and in other medical fields and cautiously extrapolate these findings to supportive and palliative care in cancer in humans. We urge patients and clinicians to recognize the potential drawbacks and dangers of cannabis, including allergic reactions, addiction/dependence, side effects, and interference with other medications. Nevertheless, we conclude that cannabis, in combination with guideline-based treatment regimens, tends to exhibit potential benefits that outweigh its risks.
We performed a review of the literature involving cannabis, cannabinoids, and marijuana for high priority symptoms of cancer and its treatments as identified by the National Cancer Institute Symptom Management and Quality of Life Steering Committee 13 : cognitive impairment, neurotoxicity, cardiovascular toxicity, fatigue, cancer-specific pain, sleep disorders, bone health toxicity, metabolic toxicity, and psychological distress. Chemotherapy-induced nausea and vomiting, loss of appetite/anorexia, and gastrointestinal (GI) distress were also included due to the historical use of cannabis for these cancer- and treatment-related ailments. The first author (A.S.K.) searched the PubMed database from the inception of the database to November 8, 2018. The results of this search are shown in Supplemental Table 1. Reference lists of recent review articles were also evaluated to identify additional trials. Only articles published in English were assessed, and results of clinical trials were prioritized.
Brief overview of the biological mechanisms of cannabis
Cannabis is a generic term used to describe plants from the genus Cannabis, as well as bioactive preparations thereof. Cannabis plants contain more than 400 secondary metabolites, many of which exert bioactive effects. Of these metabolites, two have been identified as the most bioactive: Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). Further, cannabis contains terpenoids, which are responsible for the aroma of cannabis, and flavonoids, which are believed to be responsible for the health benefits of many vegetables, spices, and other foods. 14 It appears that many of the other metabolites of cannabis can have antagonist, additive, or synergistic properties with THC in regard to some, but not all, of its effects. 14,15 The concentrations and ratios of the various phytocannabinoids (cannabinoids specific to the cannabis plant) differ depending on plant strain and growing conditions. 16,17
Endogenous cannabinoids (‘endocannabinoids,’ or cannabinoids made in the body) comprise bioactive lipids, most derived from arachidonic acid. These include arachidonoyl-ethanolamide (AEA; previously known as anandamide) and 2-arachidonoylglycerol (2-AG), among others. 18 There are two major cannabinoid receptors: cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). Cannabinoid receptors are expressed in virtually all regions of the brain and in the peripheral nervous system, with notable density in the hippocampus, amygdala, thalamus, and association regions of the cortex (e.g., cingulate). 19,20 These regions are part of interoceptive brain circuitry, which processes bodily sensations and supports mood, depression, anxiety, memory, pain, and other psychological functions (see review by Kleckner and colleagues 21 ). In other words, interoceptive brain circuitry helps translate sensation (the signal transduction from the periphery) to perception (the symptoms that patients experience and report). 22 Binding of a cannabinoid to one of these receptors leads to G-protein activation, which affects various cellular functions depending on the type of cell ( Figure 1 ). Many of the metabolites of these endocannabinoids activate a number of other receptors that are involved in inflammation, thereby implicating endocannabinoids as inflammatory regulators. 18 Further, CB1 receptors are present on the mitochondrial membrane, where activation can directly control cellular respiration, energy production, and generation of reactive oxygen species. 23,24
Mechanisms through which cannabinoids can affect cancer- and chemotherapy-related symptoms. ❶ Binding to a cannabinoid receptor. ❷ THC and other lipophilic cannabinoids can diffuse freely through the cellular membrane, where they are then transported intracellularly by fatty acid binding proteins. 25 Lipophilic cannabinoids also freely diffuse into the membranes of intracellular vesicles. 26 ❸Cannabinoids are hydrolyzed into various metabolites that can bind to CB1 and other receptors involved in immune function, cellular signaling, etc.
2-AG, 2-arachidonoylglycerol; AEA, arachidonoyl-ethanolamide; ATP, adenosine triphosphate; CB, cannabinoid; CBD; cannabidiol; P450, cytochrome P450; PPAR-α, peroxisome proliferator-activated receptor α; ROS, reactive oxygen species; THC, Δ 9 -tetrahydrocannabinol; TRPV1, transient receptor potential cation channel subfamily V member 1; Ψm, membrane potential.
Phytocannabinoids are cannabinoids that are present in the cannabis plant. The major phytocannabinoid in cannabis is THC, which is responsible for approximately 20% of the total content of the plant (by weight), 27 and 20% of the bioactivity of cannabis extracts in various assays. 17 THC directly binds CB1 and CB2. CBD is the second most studied phytocannabinoid; it has a low affinity for the CB1 and CB2 receptors per se, but it blocks the fatty-acid binding protein that transports endocannabinoids to be hydrolyzed, hence prolonging the activation of the CB1 receptor. 5,25 It also modulates other receptors such as the 5-hydroxytryptamine (5-HT1A) serotonin receptor, the peroxisome proliferator-activated receptor γ (PPAR-γ), and others. 28 CBD is thought to have a greater potential value for medicinal purposes than THC, mostly due to its lack of psychoactive properties. 29 Therefore, pharmaceutical companies and medical marijuana growers produce medicinal preparations with specific THC:CBD ratios (e.g., 1:1, 1:20). 30 There are now synthetic preparations of THC (dronabinol), CBD, THC analogs (e.g., nabilone), and CBD derivatives, though the characterization of the therapeutic value of these compounds is in its infancy. 31 Of note, the US Food and Drug Administration approved the first highly purified plant-derived compound from cannabis, CBD as Epidiolex®, in 2018, and many other preparations will likely follow.
One of the major mechanisms by which cannabinoids can elicit a therapeutic response is via the immune response. Indeed, cancer and its treatments lead to systemic elevated inflammation responsible for chemotherapy-induced symptoms including: cognitive deficiencies such as problems with attention, memory, and executive functioning; fatigue and motivational deficit; and neuropathy. 2,32 –36 Endocannabinoids are produced as part of the innate immune response, and monocytes, B cells, T cells, and other immune cells all have cannabinoid receptors. 37 Indeed, many cannabinoids have an arachidonic acid moiety, which is the precursor of many pro- and anti-inflammatory molecules. 2-AG is an important metabolic intermediate in lipid synthesis and serves as a major source of arachidonic acid in prostaglandin synthesis. 15 Eicosanoids are produced from arachidonic acid, and they function to both initiate and reduce inflammation. Whereas cyclooxygenase-2 inhibitors suppress the synthesis of eicosanoids to attenuate the ramping up of inflammatory processes, cannabinoids increase the production of eicosanoids to slow it down. 16 Several preclinical studies have shown that cannabis can inhibit the production of TNF and other cytokines in several different models and by several different mechanisms, not all of which involve cannabinoid-specific receptors. 37 –39
Cannabis and common symptoms of cancer and its treatments
Cannabis use is a promising approach to symptom management in the context of cancer and its treatments because of its multifaceted bioactivities in multiple tissues. 40 In this section, we discuss several common symptoms and side effects of cancer and its treatments with a summary of preclinical and clinical studies of cannabis in cancer patients and other clinical populations ( Table 1 ).
Cannabis for cancer- and cancer treatment-related toxicities: a summary.
|Nausea and vomiting||There is evidence that cannabis or cannabis-derived products can alleviate chemotherapy-induced nausea and/or vomiting, and an inhalable form could be better for patients unable to retain oral medications. However, most data are from the 1980s, and cannabis has not been compared with modern anti-emetic regimens.|
|Anorexia and loss of appetite||Medical cannabis and THC specifically, have led to increased appetite in humans and laboratory animals, mostly in noncancer contexts thus far.|
|Pain||Research is promising for relieving pain acutely from various sources including cancer, perhaps even to reduce the dose of opiates. However, pain surfaces via many different mechanisms and it is not yet clear what contexts in which cannabis could have an analgesic effect.|
|Chemotherapy-induced peripheral neuropathy||Evidence is promising from studies in people with HIV, trauma/surgery, and diabetes as well as cancer-related animal models, but there is not yet evidence in humans with cancer.|
|Gastrointestinal distress||There are promising data from research in patients with inflammatory bowel disease, but none yet in patients with cancer. Diarrhea can also be a side effect of cannabis use.|
|Cognitive impairment||There have not been studies with cannabis for cancer-related cognitive problems. Recreational users and patients report acute complaints in memory, attention, and executive function, though long-term effects are unclear. Some studies suggest potential benefits, especially from cannabidiol.|
|Anxiety and depression||Most research to date is epidemiological and results are unclear.|
|Sleep disorders and fatigue||Very few studies have been conducted, but limited evidence suggests that cannabis is promising for alleviation of clinical sleep disorders (not yet in patients with cancer).|
|Cardiac, metabolic, and bone health toxicities||Too few studies have been conducted to make conclusions recommending or discouraging cannabis for these purposes.|
THC, Δ 9 -tetrahydrocannabinol.
Nausea and vomiting
Chemotherapy-induced nausea and vomiting (CINV) is highly prevalent, with many common chemotherapy regimens classified as ‘highly-‘ or ‘moderately’ emetogenic. In general, modern anti-emetic regimens are extremely effective at preventing emesis, but these regimens are much less effective at controlling nausea. 41,42 In fact, control of nausea remains poor, with 40–70% of patients reporting nausea while receiving highly or moderately emetogenic chemotherapy. 43 –51 However, little attention has been directed to the concept of chemotherapy-induced nausea as a discrete symptom, despite recognition that nausea and vomiting are two related but separate entities. 52,53 Nausea and vomiting symptoms also vary over the course of chemotherapy via different mechanisms, and therefore different interventions are needed as treatment progresses. 53
The mechanism by which chemotherapeutic agents induce nausea and vomiting is fairly well understood. Chemotherapeutic agents promote excess serotonin release from enterochromaffin cells that line the GI tract, and elevated concentrations of serotonin bind to 5-hydroxytryptamine 3 (5-HT3) receptors on nearby vagal nerve afferents, which send information of excess chemicals to the brain and directly promote emesis. Further, toxicity to enterochromaffin cells can cause cell death and chronic elevation of serotonin and other secreted substances, which in turn sensitize the vagal nerve and cause delayed nausea and vomiting (reviewed by Janelsins and colleagues 34 ). The most widely used classes of anti-emetics for cancer patients are 5-HT3 receptor antagonists, and cannabinoids also directly inhibit these receptors. 54 Specifically, it is thought that CBD may act as a modulator of the 5-HT3 receptor and as an indirect agonist on the 5-HT1A autoreceptors, which ultimately reduces the availability of serotonin (5-HT3). 55
Increasing preclinical evidence suggests that the endocannabinoid system plays a role in the regulation of both nausea and vomiting. 56 Cannabinoid receptors CB1 and CB2, located within the brainstem and the GI tract, are associated with emetogenic control in rat, mouse, ferret, and shrew. 57 –59 For example, THC reduced the emetic effects of cisplatin chemotherapy induced in the least shrew. 59 In addition, CBD-induced suppression of vomiting was reversed by systemic pretreatment with a 5-HT1A antagonist, 59 suggesting that the anti-emetic effect of CBD may be mediated by activation of 5-HT autoreceptors. In a parallel mechanism, substance P may be a key neurotransmitter in chemotherapy-induced nausea and vomiting, 60,61 and cannabinoids modulated release of substance P in several preclinical studies. 62 –64 For example, THC was shown to increase substance P release in adult rat brain. 64 In addition, CB1 receptor stimulation promoted its release in adult mouse spinal cord 62 and in cultured rat dorsal root ganglion cells. 63 As substance P tends to be a key first responder to noxious stimuli (i.e. chemotherapy), modulation of this neuropeptide with concomitant chemotherapy and medicinal marijuana could help alleviate acute nausea and vomiting.
Patient claims that cannabis relieves chemotherapy-induced nausea and vomiting are widely recognized, and increasing clinical evidence supports these anecdotes. 58,65 –68 For example, in 2001, Musty and colleagues published a review of previously unpublished technical reports from six states (e.g., Tennessee 69 and New Mexico 70 ) that conducted trials of smoked cannabis. They reported that 70–100% of subjects experienced relief from nausea and vomiting, while those taking oral THC experienced a 76–88% reduction. 66 In one of the only studies performed in the 21st century, Duran and colleagues recruited 16 patients on chemotherapy who experienced chemotherapy-induced nausea or vomiting despite standard anti-emetic treatment. 71 Patients were randomized to either an oromucosal cannabis-based spray containing THC and CBD or a placebo. Those in the treatment group experienced less nausea and vomiting than those on the placebo. In addition, in 2007, Meiri and colleagues randomized patients receiving moderately to highly emetogenic chemotherapy (n = 64) to dronabinol (synthetic THC), ondansetron, both, or a placebo in addition to standard anti-emetic treatments. 72 Dronabinol performed equal to ondansetron to prevent chemotherapy-induced nausea and vomiting, with no additive effects on the combination, and all treatment groups were more effective than the placebo. Combining these data with data from the 1970s and 1980s, a 2017 report concluded that there is conclusive evidence that oral cannabinoids are effective in the treatment of chemotherapy-induced nausea and vomiting. 73
A nonoral route (e.g., inhalation, intranasal) of drug delivery is particularly important for treatment of nausea and vomiting so the drug can reliably be delivered to the target site and not emitted itself. 53 Further, intravenous drugs are not optimal for delivery at home, and delayed nausea, which is more common than acute nausea, develops >24 h after infusion and commonly occurs in patients receiving cisplatin, carboplatin, cyclophosphamide, or doxorubicin. 34 New opportunities in smoking technology are becoming available such as e-cigarettes and vaporizing devices (see Table 2 ).
The appropriate delivery system allows bioactive compounds to be supplied to target tissues at an appropriate dose and rate.
|Delivery method||Delivery options||Details||Benefits||Drawbacks|
|Inhalation||• Smoking the leaves of a cannabis plant is the most traditional method of delivery.
• Vaporizers (or ‘vape pens’) vaporize the cannabinoids while avoiding combustion and smoke inhalation. They can vaporize compounds within the cannabis plant or from extracts or purified cannabinoids (e.g. CBD)
|• Peak plasma concentration occurs 2–30 min after inhaling, and then declines over approximately 30 min to 3–4 h 4,76||• Fast alleviation of symptoms
• Particularly useful for chemotherapy-induced nausea and vomiting when oral medications could be expelled
• Allows for dose titration
|• Patients with pulmonary or thoracic cancer might need to avoid
• Could be contraindicated in patients with asthma
• Vaping reduces risk compared with smoking but still involves inhaling particulate matter
|Oral||• Cannabis and cannabinoids can be swallowed in pills or edible preparations
• Tinctures are drops or sprays that are delivered into the mouth, often sublingually to be under the tongue into the sublingual artery
|• Dronabinol (synthetic THC) is one of the only FDA-approved cannabis derivatives on the market
• Numerous edible preparations available in states where cannabis is legal (e.g. CBD confections)
• Bioactive compounds circulate anywhere from 1 to 6 h after administration
|• Slower and more prolonged onset of both psychoactive and other bioactive effects||• More intensified, problematic side effects have been documented such as sedation and psychoactive effects, 16 likely because Δ 9 -THC is metabolized in the liver into 11-OH-THC before it enters circulation, which is a potent psychoactive metabolite of THC
• THC has a low and variable bioavailability (6–20%), so proper dosing can be difficult 4
|Topical||• Lotions, creams, and ointments||• No information is available, to our knowledge, on bioavailability of cannabinoids through the skin, effectiveness, or safety 77||• Can deliver bioactive compounds directly to skin, if that is the target site (e.g. to reduce itching)||• None noted|
THC, Δ 9 -tetrahydrocannabinol; CBD, cannabidiol.
There are some limitations and gaps in the literature before cannabis-derived therapeutics can be prescribed as a first-line treatment for nausea and vomiting. For example, most of the studies evaluating the efficacy of cannabinoids were performed in the 1980s, and have not yet been compared with modern anti-emetic regimens. 74 In addition, paradoxically, an increasingly recognized symptom of cannabis use is cannabinoid hyperemesis syndrome, which presents as intractable cycles of vomiting. 75 This syndrome tends to be associated with frequent, high doses of recreational cannabis. The etiology of cannabinoid hyperemesis syndrome is largely unknown, but is expected to involve the endocannabinoid system. 75
Anorexia and loss of appetite
Decreased appetite and anorexia are ranked among the most troublesome side effects of cancer and its treatment; more than half of patients with advanced cancer experience a lack of appetite or weight loss. 78 –80 Appetite-stimulating drugs that are currently used include megestrol acetate (similar to the female hormone progesterone), metoclopramide (a gut mobility stimulator), steroids including prednisone or dexamethasone, and dronabinol (synthetic THC). All of these drugs except dronabinol are recommended for short-term use only due to potential side effects. Further, radiation therapy in head and neck cancer patients includes irradiation of the mouth and salivary glands, and many patients suffer from dysgeusia (distortion of taste), anatomical intraoral defects, or oral mucosal damage, 81 which can lead to loss of appetite and body mass.
Endocannabinoids regulate eating behavior via several biochemical pathways in the brain and the periphery: the hypothalamus and hindbrain (integrative functions), the limbic system (for hedonic evaluation of foods), the intestinal tract, and adipose tissue. 82 These pathways modulate peptides involved in appetite regulation, including ghrelin, leptin, and melanocortins. 82 Endocannabinoids AEA and 2-AG stimulate food intake in rats, 83 –85 and SR141716, a CB1 antagonist, attenuated those increases in rats 84 and induced appetite suppression in mice. 86 Medical cannabis and THC, specifically, are known to boost appetite in humans and laboratory animals. 85,87 –92
Overall, studies assessing the effects of cannabis or phytocannabinoids on appetite in cancer patients have shown benefits, although there appears to be a placebo effect, and a 2017 report found insufficient evidence to support or refute its use. 73 In one study in 469 patients with advanced cancer and documented weight loss or reduced food intake, 93 and another in 243 patients with advanced cancer and cancer-related anorexia–cachexia syndrome (CACS), 94 appetite increased in all groups including comparison groups treated with dronabinol (synthetic THC), megestrol acetate, 93 cannabis extract, and placebo, 94 suggesting that cannabis-derived products are no better than a placebo. One smaller study (n = 46) of dronabinol in advanced cancer patients demonstrated enhanced taste of food compared with placebo. 95 Appetite also improved in several other prospective or randomized studies in patients with cancer, though caloric intake was not significantly greater. 92,95
Much of the clinical research on cannabis and appetite has been performed in patients with human immunodeficiency virus (HIV), who often suffer from decreased appetite and weight loss. In three independent randomized, placebo-controlled trials, smoked cannabis and oral THC increased caloric intake and weight gain in patients with HIV compared with placebo, especially in patients who were underweight. 96 –98 Moreover, in 15 patients with Alzheimer’s disease who were refusing food, dronabinol (synthetic THC) increased body weight compared with placebo. 99
The limitations of this research thus far is that there has not yet been a randomized controlled trial to systematically evaluate the efficacy of cannabis-derived products on both appetite and weight gain as primary endpoints in patients with cancer. Future studies to this end should consider the composition of the diet (e.g., macronutrient composition) and the weight that has been gained (e.g., fat versus lean mass). Future studies will need to have appropriate control groups, including current remedies and a placebo.
More than half of all cancer patients experience moderate to severe pain. 100 Management of cancer pain has improved, generally via optimization of nonpharmaceutical practices such as exercise, 101 –104 and cognitive behavioral therapy. 105,106 However, insurance companies often do not reimburse these practices, leaving opiates as the first-line of treatment for cancer-associated pain. 107 With that said, alternatives for opiates are sought by patients because: opiates do not provide an adequate analgesic effect for some patients; the required opiate dose may lead to debilitating side effects such as constipation; there is a potential to overdose on opiates; finding the individualized, appropriate dose of opiates requires titration, which can take days or weeks; and the potential for dependence on opiates is extremely high, and patients with a high likelihood for survival from the cancer or an inclination toward addiction should avoid frequent opiate use.
The etiology of cancer-related pain is complex and not well understood. Its presentation stems from interaction between the cancer and peripheral sensory neurons (i.e., nociceptors) as well as morphological, physiological, and immunological changes that cause sensitization of the peripheral and central nervous system (CNS) as well as increases in spontaneous activity. 108 These effects vary drastically depending on the type and location of the cancer. 108 There is evidence that cannabis can affect both sensation (signal transduction in the nervous system) and perception (the experience of symptoms); therefore, studies at the biochemical, neurological, psychological, and social levels are all important. 109 Nociceptors have CB1 receptors, allowing cannabinoids to have a direct analgesic effect by modulating nociceptor activity in the periphery (i.e., sensation). CB1 and CB2 receptors throughout the nervous and immune systems allow for parallel mechanisms of cannabinoids to modulate pain sensation. In addition, there is evidence that cannabinoids potentiate the analgesic effects of opioids, thus allowing for dose-reductions of opioids. 110
Preclinical studies have demonstrated that cannabinoid receptor agonists can reduce cancer-related pain behavior, though it is unclear through which receptors the relationship is mediated. For example, WIN55,212-2, an agonist of the CB1 and CB2 cannabinoid receptors, attenuated cancer-related pain behavior in mice. 111,112 In mice, a CB2-selective agonist reduced cancer-related pain behavior. 112 However, fully blocking either of these receptors did not prevent WIN55,212-2 from having analgesic effects. 111
Anecdotal evidence suggests that recreational cannabis can alleviate cancer-related pain, 113 and two recent reviews on the effects of cannabis on cancer-related pain concluded that cannabis-derived compounds can alleviate chronic and neuropathic pain in advanced cancer patients. 113,114 Since these two reviews were published, in a 2018 prospective analysis, 92 Bar-Lev Schleider and colleagues showed that 52.9% of patients with cancer reported a pain level of 8–10 on a 10-point scale at baseline, while only 4.6% reported that intensity of pain after 6 months of cannabis treatment. Because there was no control group, it is not possible to know if cannabis per se reduced pain, or if time or other factors were involved. However, the authors concluded that cannabis appears to be a safe and effective palliative treatment for patients with cancer pain. Fallen and colleagues also conducted two randomized controlled trials with patients with cancer-related pain who were not getting adequate analgesia from opioids. 115 Compared with the control arm, those in the THC:CBD group did not experience relief from pain, though a subgroup analysis showed that participants from the United States did experience pain relief.
A 2017 analysis of five systematic reviews and several more recent trials concluded that there is substantial evidence that cannabis is an effective treatment for chronic pain in adults (not necessarily cancer patients). 73,116 Indeed, the analgesic effects of cannabis tend to be the most sought-after properties of medicinal cannabis among all patients (not necessarily cancer patients) who elect to use it. 117 –119 With that said, the authors of a 2015 systematic review concluded that, although effective, currently available cannabis-based medications reduce pain only to a modest extent, similar to other drugs on the market. 116 A review by Hill in 2015 on cannabis for the treatment of chronic pain concluded that evidence is beginning to accumulate that cannabis/cannabinoids are promising for the treatment of chronic pain, neuropathic pain, and pain from multiple sclerosis. 30 Amato and colleagues published a review demonstrating that three out of four studies showed benefits of cannabis compared with placebo in reducing pain in patients with multiple sclerosis, chronic pain, dementia, Tourette syndrome, and cancer. 65 Further, a prospective single-arm study published in 2018 followed 338 medicinal cannabis users with various chronic pain conditions. Pain intensity decreased significantly over the course of 12 months. 120
Cannabis may present itself as a promising alternative to opioids for cancer-related pain in the future, though more data are needed. Indeed, there is anatomic and physiologic evidence of an interaction between cannabinoids and opioid receptors. 121 Cannabinoids may directly and effectively target the opioid system and also work with opioids to modulate both cannabinoid and opioid pathways in tandem. 82,121 –124 In a retrospective study of 244 medicinal cannabis users with chronic pain, cannabis was associated with a 64% decrease in opiate use, fewer side effects of all drugs, and improved quality of life. 125 In another survey in 2897 medicinal cannabis users, 97% reported that they were able to reduce their dose of opiates after initiation of cannabis use. 126 However, others studies, such as a three-arm randomized controlled trial evaluating THC:CBD versus THC versus placebo for cancer-related pain, have not shown a reduction in opiate use; dosing of opiates did not change significantly over the 2-week study for any arm. 127 System-wide data corroborate reports of the use of cannabis for pain or as an analgesic potentiator: physicians in states where medicinal cannabis was legalized prescribe more than 10% fewer daily doses of pain medication, 128 and, particularly promisingly, legalization of medicinal cannabis is associated with a reduction in opioid overdoses. 129 However, a 2017 report by the National Academy of Sciences concluded that, at this point, there is not enough evidence to recommend or discourage cannabinoids in the treatment for addiction. 73
There are several limitations to the current body of literature related to pain. For example, both cancer and pain are heterogeneous manifestations with complex features that change during disease progression and treatment, making pain difficult to target. As such, treatments that work for radiation-induced pelvic pain might not work for chemotherapy-induced neuropathic pain. In addition, studies that have been performed in the United States using cannabis plants all used product from the National Institute on Drug Abuse, which differs in bioactive concentration from what is available in dispensaries, 130 and likely interacts differently with opiates and other pain medications. The placebo effect appears to be particularly strong, which is beneficial to patients in general, but makes it more difficult to study the biochemical and physiological analgesic effects of cannabis-based therapies.
Chemotherapy-induced peripheral neuropathy
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect and dose-limiting toxicity of several commonly used chemotherapeutic agents, and can lead to dosage reductions or cessation of therapy. The symptoms of CIPN primarily include abnormal sensory discrimination of touch, vibration, temperature variations, and pain. 131 A recent meta-analysis found a CIPN prevalence of 68.1% within the first month of chemotherapy, 60% within 3 months, and 30% at 6 months or later. 132 CIPN occurs most frequently with platinum-based chemotherapeutic agents (i.e., oxaliplatin and cisplatin) and taxane-based chemotherapeutic agents (i.e., paclitaxel and docetaxel). It is widely believed that cisplatin-induced neuropathy is irreversible, while taxane-induced neuropathy generally resolves but can persist for years in up to 30% of patients. 133 CIPN is notoriously difficult to treat, and treatment options remain limited, as antiepileptic or antidepressant agents used to treat other neuropathic pain conditions have not been successful in cancer patients. 134 –136
The exact mechanism(s) of CIPN and mechanisms by which cannabis might reduce CIPN and its symptoms are unknown, although recent preclinical studies have elucidated potential pathways. In one such study, a CB1/CB2 agonist reduced paclitaxel-induced thermal hyperalgesia and tactile allodynia (proxies for neuropathy) in rats. This effect was reversed by the use of a CB1 antagonist, suggesting a role for CB1 receptor in CIPN. 137 In addition, another preclinical study found the same CB1/CB2 agonist suppressed vincristine-induced mechanical allodynia (a proxy for neuropathy) through activation of both CB1 and CB2 receptors. 138 Moreover, activation of CB2 receptors partially attenuated vincristine-induced neuropathy 138 and fully attenuated paclitaxel-induced mechanical allodynia 139,140 and cold allodynia 140 in rats. Other researchers have presented evidence that CBD plays a role in reducing neuropathic pain. In one study, researchers induced neuropathy with paclitaxel, and found that subsequent administration with CBD prevented the development of cold and mechanical allodynia, with no latent neuropathy emerging after the cessation of CBD treatment. 141 In a follow-up study, lower doses of CBD were administered to rats prior to inducing neuropathy with paclitaxel. 142 Administration of CBD prevented the development of paclitaxel-induced mechanical sensitivity. This effect was reversed by administration of the 5-HT(1A) antagonist, but not with a CB1 or CB2 antagonist. Based on these results, it is possible cannabis may reduce both chemotherapy-induced nausea and vomiting and CIPN through a shared mechanism: 5-HT.
Several placebo-controlled clinical trials have examined the effect of smoked or vaporized cannabis for neuropathic pain of various etiologies, though none yet for patients with cancer or CIPN. Patients suffering from chronic neuropathic pain of various etiologies, including HIV, trauma/surgery, and diabetes, reported that smoked cannabis significantly decreased central and peripheral neuropathic pain compared with placebo. 143 –148 In addition, studies in mouse and rat models have demonstrated that THC and/or CBD reduce the quantity of circulating pro-inflammatory cytokines and alleviate neuropathic symptoms associated with constriction injury 149 and chemotherapy. 137 –142,150
CIPN is a particularly difficult symptom to treat due to its elusive etiology and largely unpredictable pattern of presentation. Currently, it is unclear if the observed effects of cannabis are due to its action on the peripheral nerves by reducing damage, on the CNS by reducing or attenuating hypersensitization, both, or other mechanisms. A variety of measures are needed to answer these questions, including both nerve conduction and patient report. It is also not yet clear if primary prevention or treatment after presentation will be the most impactful.
Chemotherapy-induced GI distress (e.g., bloating, cramps, flatulence, diarrhea, abdominal pain) is a common and understudied toxicity of cancer treatment. In fact, up to 80% of patients receiving chemotherapy report diarrhea, and approximately 16% experience constipation (up to 87% of patients with advanced cancer). 151,152 GI distress is associated with worsening quality of life, and also contributes to malnutrition, dehydration, fatigue, anxiety, depression, and other symptoms. 151,153 These symptoms can be so debilitating that 22% of patients reduce their life-saving chemotherapy doses, 28% delay treatments, and 15% terminate chemotherapy completely. GI distress and diarrhea are strongly correlated with chemotherapy dose, as well as certain chemotherapy regimens such as 5-fluorouracil and irinotecan. 151 In fact, the majority of patients on these regimens experience diarrhea and more than 30% of patients report severe (grade 3 or 4) diarrhea. 151 Furthermore, symptoms seldom resolve at the completion of chemotherapy, and GI distress persists for 10 years in some patients. 151
The mechanisms by which chemotherapy induces diarrhea are largely elusive, but cancer- and chemotherapy-induced increases in inflammatory cytokines are largely implicated. 151 In addition, microbiota are implicated in chemotherapy-induced GI distress, but it is not clear if inflammation causes disruption of microbiota, or vice versa. 154 Cannabis-derived treatments could moderate GI symptoms via inflammatory pathways, and also more directly via the endocannabinoid system, which contributes to regulation of peristalsis and gut motility both at the site of the tissue and centrally via the brain-gut axis. 155 –157 Cannabis tends to slow GI motility, 157 but also relax the bowels, allowing it to have potential effects for both diarrhea and constipation.
Dinitrobenzene sulfonic acid-induced colitis is a standard mouse model for studying inflammatory bowel disease. Pagano and colleagues examined the effects of cannabis on mucosal inflammation in this model, as well as hypermotility in a croton oil-induced mouse model of intestinal hypermotility. 155 They used four experimental conditions: high-CBD Cannabis sativa extract or pure CBD administered intraperitoneally or orally via gavage. The extract reduced the extent of pathologic damage and reduced hypermotility; pure CBD did not alleviate inflammation but reduced hypermotility. Borrelli and colleagues also explored the effects of CBD on symptoms of dinitrobenzene sulfonic acid-induced colitis in a mouse model; CBD reduced colon injury and inflammation. 158
No data are available on the efficacy for cannabis-derived products to prevent or treat cancer- or chemotherapy-induced gastrointestinal distress in humans, but cannabis has been used in traditional medicine for centuries to alleviate both diarrhea and constipation, 159 and there have been quite a few population-based surveys examining patterns of cannabis use among patients with irritable bowel syndrome or inflammatory bowel disease. Participants with inflammatory bowel disease, ulcerative colitis, and Crohn’s disease are more likely to have used cannabis or hashish compared with individuals without the disease specifically to help alleviate their symptoms (e.g., abdominal pain, diarrhea, loss of appetite). 160 –164 Interestingly, in Massachusetts, Merker and colleagues showed that recreational and medicinal use of cannabis among approximately 300 patients with inflammatory bowel disease nearly doubled from 2012, before medical cannabis was legalized, to 2017, after it was legalized. 165 Despite the empirical benefits of cannabis for abdominal pain and other forms of GI distress, 161 there have not been many randomized controlled trials evaluating cannabis for GI distress; a review of the literature by Ahmed and colleagues and the National Academy of Sciences could not definitively conclude that cannabis was able to mitigate symptoms of inflammatory bowel disease. 73,166
This body of literature is very much in its infancy and more clinical trials are needed. Further research should explore the effects of cannabis on various aspects of gut health in patients with cancer, including inflammation and the microbiome, especially in regard to chemotherapy insults. GI distress is often a side effect of treatment, and it is often difficult to accurately attribute symptoms to the cancer or a drug (e.g., constipation is a common side effects of opiates). 151 Owing to the direct delivery, this is one symptom where ingestion of cannabis products might be more reliable, predictable, and beneficial than inhalation, but more studies are needed determine the efficacy of edibles for GI distress.
Cancer-related cognitive impairment is one of the most common symptoms of patients undergoing cancer treatment for non-CNS disease. Indeed, up to 30% of patients experience cancer-related cognitive impairment even before treatment, and this number increases to 75% during treatment. 32 Furthermore, cognitive impairment affects cancer patients across multiple cognitive domains (e.g., memory, executive function) for at least 6 months postchemotherapy and some experience longer term cognitive problems. 167 Cognition relies on the function of many interrelated neural systems, with complex processes. 24,32 The impact of cancer and cancer treatments may cause direct or indirect effects on CNS function. 168 Proposed biologic mechanisms include inflammation, neuroinflammation, mitochondrial dysfunction, neural cell genesis disruption, and disruption of neural network connectivity (e.g., synaptic connections). 32,169 –171 Cognitive behavioral therapy, cognitive brain training, and physical activity have shown promise for managing cancer- and chemotherapy-related cognitive impairment. 32,172 However, these approaches come with barriers, including time, availability, preference, and physical abilities. Also, modafinil and methylphenidate have shown promise, but further research is needed to confirm their efficacy. 172 –176
Many preclinical rodent models, including wild type as well as those for neurodegenerative diseases (e.g., Alzheimer’s disease), neuro-inflammatory disorders (e.g., meningitis), and others, 177 have been used to assess the effects of cannabis and cannabinoids on cognition, but there have not yet been any studies in cancer or chemotherapy-based models. It is clear that the endocannabinoid system is involved in cognitive function. 178 In general, moderate-to-large doses of THC and other cannabinoid receptor agonists appear to lead to acute impairment in memory, attention, and working memory in animal models, but there is evidence that these effects are merely transient. 178,179 On the other hand, CBD could be beneficial to cognitive function. 177,178 In addition, the endocannabinoid system is significantly affected by aging, and preclinical evidence shows that cannabinoids can reverse age-related cognitive impairment. 76,180 For example, CBD reversed the neurodegenerative effects of iron in a rat model 181 and attenuated brain ischemia-induced cognitive deficits in a mouse model. 182 In addition, in older mice, a chronic low dose of THC restored learning 76 and a single low dose of THC improved spatial learning and memory. 180 Results have been mixed on the effects of cannabis on Alzheimer’s symptoms, suggesting interactions between cannabis and genetic factors; for example, CBD and/or THC alleviated Alzheimer’s-like symptoms in mice genetically predisposed to the disease, although the cannabinoids impaired cognition in wild type mice. 177,183 –185 Myers and colleagues studied the effects of cannabinoids on cognition in wild type mice. 186 They saw that THC and/or a CB1/CB2 receptor full agonist led to cognitive impairment in a maze task (assessing spatial memory) but not in a conditional discrimination task (assessing learning); CBD had fewer effects on cognition. Similarly, Murphy and colleagues showed that THC impaired object/working memory in adult mice; cotreatment with CBD prevented these impairments, and CBD alone led to no impairment. 76,187 A 2017 systematic review of 18 studies in mice, rats, or Rhesus monkeys concluded that preclinical models point to CBD improving cognitive function in regard to learning and memory. 177
In humans, there have not yet been any studies using cannabis that test cognitive function as a primary outcome in patients with cancer. In general, acute cognitive impairment has been broadly cited as a side effect of cannabis use, including memory loss and reduced ability to concentrate and learn. 188,189 However, there is very little research on whether the acute cognitive side effects are generally tolerable to patients with cancer, and no research on whether cannabis or cannabis-derived products can treat late-effects of cancer and its treatments (especially chemotherapy). Bar-Sela and colleagues followed cancer patients who had obtained a medical marijuana license during their cancer treatment, and, overall, the only negative effect of cannabis they observed was that patients’ memories declined with 6–8 weeks of cannabis use. 190 However, these researchers performed a follow-up prospective study among patients with advanced cancer undergoing chemotherapy and demonstrated improvement in executive function among patients who opted to use cannabis treatment over a 3-month period. 191 There have not yet been any studies on the effects of CBD to treat chemotherapy-induced cognitive impairment, though a 2017 systematic review of nine clinical trials (participants included healthy volunteers, patients with multiple sclerosis, patient with schizophrenia, and others) demonstrated that CBD tends to have no effect or a benefit in memory, attention, executive function, processing speed, and other measures of cognition. 177 Also, cannabis has shown promise in treating Alzheimer’s disease, a disorder associated with progressive memory loss. 184
Epidemiological research shows an association between chronic cannabis use and long-term, more permanent, impairments, though aging and educational level are major confounding factors not adequately considered. 192,193 Similarly, chronic cannabis use, especially in adolescents, leads to a decline in neurophysiological function (reviewed by Broyd and colleagues 194 ). In cross-sectional studies, recreational cannabis is associated with defects in brain structure, especially in adolescents. 195 Thus, clinicians should use greater caution in discussions of cannabis with adolescent patients with cancer than with adult patients.
All in all, there could be unappreciated benefits of specific types of cannabinoids (especially CBD) for cognitive function in specific populations of patients with cancer, but the literature is currently very limited. Indeed, cannabis can be anti-inflammatory, 18 and could therefore theoretically attenuate and inflammatory-mediated cognitive impairment. 32,37 Controlled preclinical studies are needed to optimize the dose and type of cannabis/cannabinoids to maximize the beneficial effects seen in preliminary data while minimizing the acute toxicities. More research should also explore individual genotypes 185 that could exacerbate or benefit cannabis-induced effects on cognition.
Anxiety and depression are common reactions to the cancer and treatment experience, are often linked in the construct of ‘psychological distress,’ and are considered a sixth vital sign in cancer care. 196 –198 While a majority of patients experience some level of anxiety and depression after a cancer diagnosis, about one-third of patients experience severe and unremitting psychological distress that requires clinical treatment. 199 Anxiety can manifest as worry, difficulty concentrating, poor sleep quality, recurrent panic attacks, and other symptoms, while signs of depression include listlessness, changes in appetite and energy levels, and suicidal ideation. Even after treatment, the prevalence of depression and anxiety are greater in cancer survivors than in the general population. 196,197 Current treatments include support groups to discuss feelings, cognitive behavioral therapy to learn coping strategies, exercise, and medication (often in conjunction with therapy). 104,200
The biological underpinnings of both anxiety and depression have not been elucidated, 197 but the endocannabinoid system is involved in mood regulation 201,202 and cannabis-derived treatments could theoretically modulate the development or progression of mood disorders. There have not been any preclinical studies evaluating cannabis-derived treatments for cancer- or treatment-related anxiety or depression, but there is promising evidence for CBD as a treatment for generalized anxiety disorder in rodents (review: 203 ) For example, CBD alleviated anxiety-like behaviors in mice subjected to chronic unpredictable stress. 204,205 In addition, THC increased anxiolytic-like effects while CBD prevented anxiolytic effects in response to foot-shock stress in rats. 206
In humans, cannabis has exhibited a broad therapeutic potential across a range of psychiatric disorders. 203 Anxiety and depression, along with pain, are the top three reasons why people in the general population use cannabidiol, 207 and anxiety and depression are common symptoms for which patients with cancer seek medical cannabis. 119,208 No studies to our knowledge have assessed cannabis for mitigating anxiety or depression in cancer patients as a primary aim, though there have been several longitudinal studies following patients who elected to use medicinal cannabis during their cancer treatment. 208,209 Patients in these studies tended to experience alleviation of their symptoms, though anxiety was reported as a side effect in some patients 209 and as a withdrawal symptom in some patients upon ceasing use. 208
The noncancer literature is mixed as to whether cannabis is associated with increased or decreased depression and anxiety. Randomized clinical trials among clinical populations with exploratory measures of anxiety or depression suggest reduced or no effect compared with placebo for anxiety and depression among patients with cancer, 209 Alzheimer’s disease, 99 or diabetes. 210 Systematic reviews in healthy populations from 2003 211 and 2018, 212 a large prospective study in 2007, 213 and a meta-analysis in 2014 214 suggested that heavy cannabis use is associated with increased anxiety and depression symptoms among some users, although all studies discussed confounding factors and cautioned against making causal inferences. A recent review by Twomey, 215 however, concluded that cannabis poses no more than a minor increased risk for anxiety, citing publication bias and low-quality studies for contrary conclusions, especially in studies published before approximately 2007. Indeed, the vast majority of studies to date have evaluated associations between recreational cannabis (ab)use and anxiety and depression, where it is very likely that participants’ symptoms and environment encourage them to use cannabis for self-treatment; therefore, these studies are limited in the generalizability to patients with cancer. Indeed, several surveys indicate that cannabis alleviates symptoms of depression in a variety of recreational and medical users. 208,216 These discrepancies might stem from THC promoting anxiety while CBD alleviates it, or a much more complex interaction of bioactive compounds might be at play. 217 –219 Of note, a CB1 receptor antagonist, SR 141716A or rimonabant, was available in Europe as a treatment for obesity from 2006 to 2008; 220 it was then removed worldwide because of high levels of anxiety, nightmares, depression, and increased suicidality. 82,221,222 These data suggest that CB1 activity reduces anxiety and promotes positive affect.
Overall, the literature on use of cannabis for anxiety and depression is currently limited in that much of the data are epidemiological, both in clinical populations and in healthy individuals, and there are many confounding factors. In addition, depression and anxiety are both normal and common responses to a cancer diagnosis, and therefore diagnosing clinical levels of anxiety and depression and studying treatments to address these levels in the context of cancer is difficult. 197 More studies are sorely needed in preclinical models and in humans to assess the effects of individual cannabinoids and combinations of cannabinoids on cancer- and treatment-related anxiety and depression.
Sleep disorders and fatigue
Up to 80% of patients with cancer experience trouble sleeping. 223 In fact, three times more patients with cancer have insomnia compared with the general population. 223 Inflammation and metabolic dysregulation are potential contributing mechanisms for disrupted circadian rhythms. 224 Sleep disorders (e.g., insomnia, poor sleep quality) are also highly associated with cancer-related fatigue, 223,224 one of the most common and debilitating side effects of cancer and its treatment. 225 Thus, both symptoms are discussed here.
The endocannabinoid system is integrated into circadian rhythm and sleep-wake cycles. For example, in rats, AEA is higher in the dark phase of the dark-light cycle, and 2-AG is higher during the light in areas of the brain related to sleep (reviewed by Prospero-Garcia and colleagues 226 ). In addition, the expression of CB1 receptors in the cerebral cortex of rats undergoes diurnal fluctuations, as does CB1 receptor mRNA concentrations in pertinent brain regions. 226,227 In humans, similar patterns have been observed, where 2-AG peaks at approximately 13:00 and reaches its minimum at approximately 02:00, in the middle of the night. 228 Preclinical studies with exogenous cannabinoids have suggested that endocannabinoids regulate circadian rhythm, rather than other activities of the sleep–wake cycle affecting cannabinoid concentration and activity. 226 CBD in particular may help induce sleep, with less of a subsequent ‘hangover’ effect than common sleep aids such as benzodiazepines. 229,230
No studies, to our knowledge, have specifically assessed cannabis in humans as a treatment for sleep disorders or fatigue, cancer-related or otherwise, as a primary aim. However, in studies among patients with irritable bowel disease, 160 Crohn’s disease, 231 Parkinson’s disease, 232 multiple sclerosis, 232 and post-traumatic stress disorder (PTSD), 233 for whom fatigue is a serious issue, users of cannabis or hashish (recreational or medicinal) reported less fatigue than patients who did not use cannabis. Similarly, a THC–CBD oromucosal spray reduced sleep disturbances in patients with multiple sclerosis, 234 and a recent report concluded that there is moderate evidence that cannabinoids, primarily nabiximols, are an effective treatment to improve short-term sleep outcomes in individuals with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis. 73
The use of cannabis for sleep disorders and to alleviate fatigue is limited in ways similar to other sleep aids in that patients could become dependent. 230 In addition, the literature thus far has not involved patients with cancer, and therefore the mechanisms by which fatigue and sleep disorders arise might be affected by endocannabinoid regulators differently than fatigue/sleep disorders from other conditions.
Metabolic, cardiovascular, and bone health toxicity
Many modern chemotherapy agents are associated with cardiotoxicity, including congestive heart failure, myocardial infarction, systemic hypertension, and others; 235 metabolic toxicity including declining insulin sensitivity, dysregulated circulating lipids, loss of skeletal muscle mass (i.e., cachexia), and overall worsening metabolic profiles; 236 and bone health toxicities including reduced bone mineral density and increased risk of osteoporotic fractures. 237 Indeed, more and more patients are surviving cancer, but many of these patients have an increased risk for morbidities and mortality from cardiovascular and metabolic diseases. Via the endocannabinoid system, inflammation, and other pathways, cannabinoids have the potential to modulate cardiovascular function, 238,239 bioenergetics, 240 bone formation, 241 and many other metabolic processes.
There have not been any studies, to the best of the authors’ knowledge, that have assessed the effects of cannabis on cancer- and treatment-related cardiovascular, metabolic, or bone toxicities in humans. However, CBD protected against the doxorubicin-induced effects on mitochondrial function and biogenesis, which precipitate declines in cardiovascular health, in mice. 242 In addition, several but not all epidemiological studies have shown that current marijuana users had lower fasting insulin levels than former or never users. 243 –245 A 2016 review concluded that there is not enough evidence to recommend or discourage the use of cannabinoids for the treatment of cancer-related cachexia. 243,246 In regard to bone health, the endocannabinoid system plays a major role in regulating bone metabolism, 247 and preclinical mouse models have shown that AM1241, a cannabinoid type 2 receptor agonist, reduced bone loss, bone pain, and the incidence of cancer-induced bone fractures while suppressing cancer growth. 248,249
In brief, the therapeutic benefit and mechanistic insight into cannabis for these side effects is particularly limited, and future research is sorely needed to evaluate the role of cannabis and cannabinoids in the etiology of cardiovascular, metabolic, and bone toxicities.
Adverse side effects
In general, cannabis is well tolerated, often with pleasant side effects and few and minor short- and long-term negative side effects. 4 Acutely, cannabis causes strong psychoactive effects, which are chiefly attributed to THC. This is the ‘high’ that recreational cannabis users are seeking, and these effects include euphoria, relaxation, alterations in perception, and time distortion. 250 However, anxiety, paranoia, and panic attacks are also side effects of THC, especially in first-time users and with particularly high doses. 250 Cognitive abilities such as attention and memory can also be compromised. Moreover, cannabis use can impair judgment and reaction time, thus reducing the ability to operate a motor vehicle. 251 –253 Unlike THC, CBD lacks psychoactive properties and attenuates the psychoactive effects of THC administered simultaneously 254 (reviewed by Abrams and Guzman 4 ). But CBD does have potential side effects including diarrhea and drowsiness. 255 Frequent high doses of recreational cannabis has been associated with cannabinoid hyperemesis syndrome, or intractable vomiting. 75 Toxicities of the lung and heart have been reported but are rare. 256
Allergies to cannabis have been reported. These allergic reactions are IgE-mediated and can vary in severity depending on the route of exposure. For example, smoking or vaporizing can lead to rhinitis, conjunctivitis, and asthma, while direct skin contact can lead to hives and contact dermatitis, and ingesting it can lead to anaphylaxis. 257 Cannabis use has been associated with an increased risk for ischemic stroke in young adults. 258
Cannabis use also has documented long-term adverse effects. Chronic cannabis users tend to have respiratory problems and may be more susceptible to respiratory infections. 250 Preclinical evidence demonstrates that chronic cannabis use can have negative effects on reproduction for both men and women, including low testosterone, impaired sperm motility and viability, and disruption of the ovulatory cycle. 250 Long-term use can lead to cardiovascular issues, especially in middle-aged and older adults, including angina and exacerbation of cardiovascular disease. 259,260 An association between cannabis use and schizophrenia has been well documented, especially when use is initiated at a young age. However, a recent sophisticated two-sample Mendelian randomization study concluded that, while causation might be occurring in both directions, it is more likely that schizophrenia risk causes cannabis use, rather than vice versa. 261 Further, there is evidence of associations between habitual cannabis use and long-term cognitive problems. 192,193 Heavy cannabis use is also associated with low bone mineral density and increased risk of osteoporotic fractures, perhaps through negative effects on mesenchymal stem cells and osteogenesis. 247,262 Addiction is a concern among some prescribers and, although approximately 9% of long-term recreational users of cannabis become addicted, 255 studies among patients with either cancer or AIDS found that treatment with THC did not lead to addiction or dependency. 82 Furthermore, heavy cannabis use disrupts sleep, and cannabis use to reduce sleep latency could become habit-forming; therefore, patients should use caution and frequently discuss their patterns of use, dose, motivations, and symptoms/side effects with their treatment team. 263
There are many other dangers of recreationally sold cannabis and cannabinoids due to the currently unregulated market. Synthetic cannabinoids and ‘dabs,’ inhalable concentrates that comprise a high concentration of THC, can impose serious psychotic, neurotoxic, cardiotoxic, and renal side effects. 264,265 Moreover, cannabis plants and products largely remain untested for contaminants including fungi (mold), bacteria, heavy metals, and pesticides, as well as adulterants. 266,267 With that said, more and more States are implementing stringent testing standards to uphold the safety of their products. Considering patients with cancer are already immune-compromised, contaminated and adulterated products could cause more harm than good.
Links between cannabis and cancer
With the strong evidence of association between tobacco use and cancer 268 –270 and the inherent similarities of tobacco and cannabis, it is important to assess the impact of cannabis use on cancer risk, progression, and recurrence. However, the available data among these relationships is scarce and equivocal. 73 There may be a relationship between current, frequent, or chronic cannabis use and the incidence of nonseminoma-type testicular germ cell tumors, 271 though evidence is lacking for incidence of all other cancers at this point. 73 Owing to the recent introduction of medical marijuana to the clinic, studies on cannabis and cancer progression and recurrence are largely absent.
There is also a real possibility that cannabis and cannabis-derived treatments can interact with cancer treatments such as chemotherapy and immunotherapy. 272 For example, Taha and colleagues recently published a retrospective study among patients with advanced melanoma, non-small cell lung cancer, or renal clear cell carcinoma on immunotherapy. This study was conducted in Israel, where cannabis use is more prevalent; 140 patients on immunotherapy were observed, 51 of whom elected to use cannabis. They showed that the use of cannabis during treatment reduced the response rate to immunotherapy. 273
Practical application in the clinic
The social and political climate is increasing patients’ and clinicians’ interest in cannabis for treatment of cancer-related symptoms. However, because of the extreme dearth of research on cannabis among patients with cancer, data are as yet insufficient to recommend cannabis instead of any current treatments. 68 With that said, minimal drug–drug interactions have been reported, side effects tend to be mild, and very preliminary reports indicate that cannabinoids tend to have anticancer rather than procancer effects, 40,73,274,275 so it is reasonable to try cannabis in addition to guideline-based treatments. Table 3 serves as a communication guide for clinicians and patients to determine if and how cannabis could be considered in cancer care, and Table 2 describes the most common delivery mechanisms (inhalation, oral consumption, and topical) though extremely scant research has been done to evaluate the bioavailability of cannabinoids in most forms that are publicly available at dispensaries. 276 Clinicians should emphasize that patients should not forgo evidence-based therapies in favor of cannabis, as the risks and benefits of cannabis are still being discovered. Clinicians and patients also need to be aware that there may be yet undiscovered interactions between cannabis and the cancer, as well as negative drug–drug interactions (e.g., nivolumab immunotherapy and cannabis, 273 valproic acid and CBD 255 ). Over the next several years and decades, different forms of cannabis and cannabinoids will likely surface as more efficacious for different symptoms. Users should also be aware that the ratios of the bioactive compounds vary between plant strains and growth conditions, and therefore the therapeutic benefits and risks of side effects might not be predictable (even with repeat purchasing of the ‘same’ product), especially in the young cannabis market.
Discussion topics to guide clinical recommendations for cannabis.
|Patient’s symptoms||There is established evidence for chemotherapy-induced nausea and vomiting, but trials comparing cannabis to modern antiemetic regimens are limited. Limited evidence supports consideration of cannabis for loss of appetite, pain, neuropathy, gastrointestinal distress, sleep disorders, and fatigue. Data available for cognitive impairment, anxiety, and depression are ambiguous.|
|Patient’s prior use||Prior experiences may have revealed the presence of severe allergies or side effects (e.g. paranoia). If prior use was decades ago, caution users that THC concentrations in cannabis plants have increased (see article by ElSohly and colleagues, and references within 275 ).|
|Patient expectancy for effectiveness of cannabis||High expectancy could lead to placebo effects.|
|Patient preference||Does the patient prefer a pill versus smoking or vaping?|
|Type||Cannabis sativa has a greater THC concentration, while Cannabis indica has a higher CBD concentration. The ‘entourage effect’ promotes the use of whole plant-derived products rather than extracts. This theory proposes that cannabis has been cultured to achieve advantageous ratios of cannabinoids, and there is interactive synergy between cannabis compounds themselves and innate human systems that promote bioactive benefits and minimize side effects. 279|
|Delivery system||Oral preparations will take longer to take effect but will have prolonged activity. Due to variation in intestinal absorption, inhalation is easier to dose. Oromucosal sprays are also available.|
|Dosing||The typical oral dose of THC can range from 2 to 60 mg/day, both recreationally and as medicinal cannabis. 4,259,280 Encourage patients to ‘start low and go slow.’ Use answers from previous questions to inform recommendations for total mg/dose and doses/day versus ‘as needed’ as well as time of day.|
|Risks||Information is currently scant, especially in regard to cancer. In general, users may experience acute psychoactive effects, anxiety, paranoia, panic attacks, cognitive impairment, judgment problems, decreased reaction time, allergy, asthma, sleep problems, etc.|
|Contraindications||There is currently minimal information. Drug inserts often recommend avoidance by patients with severe cardiovascular disease, patients with a history of schizophrenia or other psychosis, children and adolescents, and women who are pregnant or breastfeeding. Encourage patients to work with a pharmacist who is familiar with cannabis in order to avoid and quickly identify any potential drug–drug interactions.|
|Where to get it||Licensed dispensaries in your home country and state. In some areas patients might need to first be certified by their oncologist or palliative care physician.|
THC, Δ 9 -tetrahydrocannabinol; CBD, cannabidiol.
In addition, of the studies that have been performed in the US, all of them that used the cannabis plant (vaporized or smoked) procured it from the National Institute on Drug Abuse. 73 However, this strain varies drastically from the cannabis that is currently available (legally and illegally) in concentrations of THC, CBD, and other bioactive compounds. 128,277,278 Indeed, US federally supplied cannabis for research purposes cannot be used to assess the efficacy of cannabis that is marketed and used for any given symptom from cannabis dispensaries.
It is our hope that research will accelerate to meet the needs of patients and clinicians in this rapidly growing field. Cancer is not one disease but a heterogeneous class of diseases that vary greatly in progression and symptom burden. In addition, current treatments vary drastically in their effectiveness against the cancer as well as their side-effect profile. Therefore, ‘medical marijuana’ will likely quickly evolve into more granular treatments for more specific ailments as evidence supporting and contraindicating its use accumulates.
There are, to date, very few studies evaluating the use of cannabis and cannabinoids to alleviate side effects of cancer and cancer treatments in humans. Regulatory barriers need to come down so that researchers have adequate access to cannabis in the US. 276 Studies looking specifically at certain symptoms including CIPN, cognitive impairment, anxiety, depression, sleep disorders, and fatigue are sorely needed. Studies for palliative use need only focus on short-term toxicities, but supportive care studies will need to incorporate longer timelines. Researchers need to be cognizant of the wide range in the presence and severity of cancer-related symptoms, adverse effects, and unknown interactions with other medications. 94 A well-documented placebo effect needs to be accounted for in research designs. 94,95 The current literature is critically limited in that many cross-sectional studies are performed at medical marijuana dispensaries, which are biased toward patients who experience benefits, and many cannabis studies are prospective, thereby preventing assessment over time compared with a control. In addition, especially in regards to chemotherapy-induced nausea and vomiting, cannabis has not been compared with modern treatments. Further research not just describing the efficacy but also elucidating the mechanism of action of cannabis will help optimize more targeted interventions on specific symptoms and populations.
Cannabis offers many opportunities for supportive and palliative care in cancer, and recent changes in the social climate and legalization of cannabis will hopefully facilitate randomized studies to more accurately weigh the risks and benefits of cannabis use and optimize dose and administration methods. Currently, clinical evidence in populations with cancer is beginning to emerge to support the use of cannabis for treating chemotherapy-induced nausea and vomiting, loss of appetite, pain, and chemotherapy-induced peripheral neuropathy; data from other populations suggest that cannabis could be used to potentially alleviate gastrointestinal distress, anxiety, and sleep disorders ( Table 1 ). However, there are not yet data available to specify the optimal cannabis-derived treatment, dose, or delivery system. Clinicians should stay up-to-date with cannabis regulations and guidelines, 68,281 and work with patients within their preferences to alleviate symptoms. 282 Indeed, 58% of patients wish they had more information on the benefits and risks of medical cannabis, 283 so clinicians should have go-to references available for patients. Cannabis has the potential to quickly assume a large role in medicine over the next decade, and scientists and clinicians have both opportunities and responsibilities to learn and disseminate its intricacies.
Supplemental material, Suppl-Table-1 for Opportunities for cannabis in supportive care in cancer by Amber S. Kleckner, Ian R. Kleckner, Charles S. Kamen, Mohamedtaki A. Tejani, Michelle C. Janelsins, Gary R. Morrow and Luke J. Peppone in Therapeutic Advances in Medical Oncology
We thank Dr Susan Rosenthal for her editorial assistance and the thoughtful feedback from the reviewers.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported in part by NIH/NCI UG1CA189961 to G.R.M. and Karen M. Mustian, NIH/NCI K07CA221931 to I.R.K, NIH/NCI K07CA168911 to L.J.P., and NIH/NCI R01CA200579 to L.J.P.
Conflict of interest statement: The authors declare no conflicts of interest. M.A.T. obtained research support from Bayer Pharmaceutics, but that collaboration is not relevant to this work.
Supplemental material: Supplemental material for this article is available online.
Amber S. Kleckner, Cancer Control and Survivorship, University of Rochester Medical Center, CU 420658, 265 Crittenden Blvd., Rochester, NY 14642, USA.
Ian R. Kleckner, Cancer Control and Survivorship, University of Rochester Medical Center, Rochester, NY, USA.
Charles S. Kamen, Cancer Control and Survivorship, University of Rochester Medical Center, Rochester, NY, USA.
Mohamedtaki A. Tejani, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
Michelle C. Janelsins, Cancer Control and Survivorship, University of Rochester Medical Center, Rochester, NY, USA.
Gary R. Morrow, Cancer Control and Survivorship, University of Rochester Medical Center, Rochester, NY, USA.
Luke J. Peppone, Cancer Control and Survivorship, University of Rochester Medical Center, Rochester, NY, USA.
1. Griffen AM, Butow PN, Coates AS, et al. On the receiving end V: patient perceptions of the side effects of cancer chemotherapy in 1993 . Ann Oncol 1996; 7 : 189–195. [PubMed] [Google Scholar]
2. Vichaya EG, Chiu GS, Krukowski K, et al. Mechanisms of chemotherapy-induced behavioral toxicities . Front Neurosci 2015; 9 : 131. [PMC free article] [PubMed] [Google Scholar]
3. American Cancer Society. Cancer treatment and survivorship facts and figures . Atlanta: American Cancer Society, 2017. [Google Scholar]
4. Abrams DI, Guzman M. Cannabis in cancer care . Clin Pharmacol Ther 2015; 97 : 575–586. [PubMed] [Google Scholar]
5. Abrams DI. Integrating cannabis into clinical cancer care . Curr Oncol 2016; 23 : S8–S14. [PMC free article] [PubMed] [Google Scholar]
6. Saadeh CE, Rustem DR. Medical marijuana use in a community cancer center . J Oncol Pract 2018; 14 : 557 , e556–e578. [PubMed] [Google Scholar]
7. Martell K, Fairchild A, LeGerrier B, et al. Rates of cannabis use in patients with cancer . Curr Oncol 2018; 25 : 219–225. [PMC free article] [PubMed] [Google Scholar]
8. Braun IM, Wright A, Peteet J, et al. Medical oncologists’ beliefs, practices, and knowledge regarding marijuana used therapeutically: a nationally representative survey study . J Clin Oncol 2018; 36 : 1957–1962. [PMC free article] [PubMed] [Google Scholar]
9. Amato L, Minozzi S, Mitrova Z, et al. Systematic review of safeness and therapeutic efficacy of cannabis in patients with multiple sclerosis, neuropathic pain, and in oncological patients treated with chemotherapy . Epidemiol Prev 2017; 41 : 279–293. [PubMed] [Google Scholar]
10. Davis MP. Cannabinoids for symptom management and cancer therapy: the evidence . J Natl Compr Canc Netw 2016; 14 : 915–922. [PubMed] [Google Scholar]
11. Huang YH, Zhang ZF, Tashkin DP, et al. An epidemiologic review of marijuana and cancer: an update . Cancer Epidemiol Biomarkers Prev 2015; 24 : 15–31. [PMC free article] [PubMed] [Google Scholar]
12. Kramer JL. Medical marijuana for cancer . CA Cancer J Clin 2015; 65 : 109–122. [PubMed] [Google Scholar]
13. National Cancer Institute. 2015 strategic priorities: symptom management & quality of life steering committee , https://www.cancer.gov/about-nci/organization/ccct/steering-committees/2015-SxQoLSC-StrategicPriorities. (accessed 25 February 2017).
14. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects . Br J Pharmacol 2011; 163 : 1344–1364. [PMC free article] [PubMed] [Google Scholar]
15. Lu HC, Mackie K. An introduction to the endogenous cannabinoid system . Biol Psychiatry 2016; 79 : 516–525. [PMC free article] [PubMed] [Google Scholar]
16. Carter GT, Flanagan AM, Earleywine M, et al. Cannabis in palliative medicine: improving care and reducing opioid-related morbidity . Am J Hosp Palliat Care 2011; 28 : 297–303. [PubMed] [Google Scholar]
17. Hillig KW, Mahlberg PG. A Chemotaxonomic analysis of cannabinoid variation in cannabis (cannabaceae) . Am J Bot 2004; 91 : 966–975. [PubMed] [Google Scholar]
18. Turcotte C, Chouinard F, Lefebvre JS, et al. Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites . J Leukoc Biol 2015; 97 :1049–1070. [PubMed] [Google Scholar]
19. Glass M, Dragunow M, Faull RLM. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain . Neuroscience 1997; 77 : 299–318. [PubMed] [Google Scholar]
20. Marsicano G, Lutz B. Neuromodulatory functions of the endocannabinoid system . J Endocrinol Invest 2006; 29 : 27–46. [PubMed] [Google Scholar]
21. Kleckner IR, Zhang J, Touroutoglou A, et al. Evidence for a large-scale brain system supporting allostasis and interoception in humans . Nat Hum Behav 2017; 1 : pii: 0069. [PMC free article] [PubMed] [Google Scholar]
22. Kleckner IR, Quigley KS. An approach to mapping the neurophysiological state of the body to affective experience , In: Russell LFBJ. (ed.) The psychological construction of emotion . New York: Guilford, 2014. [Google Scholar]
23. Benard G, Massa F, Puente N, et al. Mitochondrial CB(1) receptors regulate neuronal energy metabolism . Nat Neurosci 2012; 15 : 558–564. [PubMed] [Google Scholar]
24. Hebert-Chatelain E, Reguero L, Puente N, et al. Cannabinoid control of brain bioenergetics: exploring the subcellular localization of the CB1 receptor . Mol Metab 2014; 3 : 495–504. [PMC free article] [PubMed] [Google Scholar]
25. Elmes MW, Kaczocha M, Berger WT, et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) . J Biol Chem 2015; 290 : 8711–8721. [PMC free article] [PubMed] [Google Scholar]
26. Reggio PH. Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown . Curr Med Chem 2010; 17 : 1468–1486. [PMC free article] [PubMed] [Google Scholar]
27. Niesink RJ, Rigter S, Koeter MW, et al. Potency trends of delta9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005–15 . Addiction 2015; 110 : 1941–1950. [PubMed] [Google Scholar]
28. Campos AC, Fogaca MV, Sonego AB, et al. Cannabidiol, neuroprotection and neuropsychiatric disorders . Pharmacol Res 2016; 112 : 119–127. [PubMed] [Google Scholar]
29. Cunha JM, Carlini EA, Pereira AE, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients . Pharmacology 1980; 21 : 175–185. [PubMed] [Google Scholar]
30. Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review . JAMA 2015; 313 : 2474–2483. [PubMed] [Google Scholar]
31. Morales P, Reggio PH, Jagerovic N. An overview on medicinal chemistry of synthetic and natural derivatives of cannabidiol . Front Pharmacol 2017; 8 : 422. [PMC free article] [PubMed] [Google Scholar]
32. Janelsins MC, Kesler SR, Ahles TA, et al. Prevalence, mechanisms, and management of cancer-related cognitive impairment . Int Rev Psychiatry 2014; 26 : 102–113. [PMC free article] [PubMed] [Google Scholar]
33. Janelsins MC, Mustian KM, Palesh OG, et al. Differential expression of cytokines in breast cancer patients receiving different chemotherapies: implications for cognitive impairment research . Support Care Cancer 2012; 20 : 831–839. [PMC free article] [PubMed] [Google Scholar]
34. Janelsins MC, Tejani MA, Kamen C, et al. Current pharmacotherapy for chemotherapy-induced nausea and vomiting in cancer patients . Expert Opin Pharmacother 2013; 14 : 757–766. [PMC free article] [PubMed] [Google Scholar]
35. Bower JE. Cancer-related fatigue—mechanisms, risk factors, and treatments . Nat Rev Clin Oncol 2014; 11 : 597–609. [PMC free article] [PubMed] [Google Scholar]
36. Williams AM, Shah R, Shayne M, et al. Associations between inflammatory markers and cognitive function in breast cancer patients receiving chemotherapy . J Neuroimmunol 2018; 314 : 17–23. [PMC free article] [PubMed] [Google Scholar]
37. Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics . Nat Rev Immunol 2005; 5 : 400–411. [PubMed] [Google Scholar]
38. Blanchard DK, Newton C, Klein TW, et al. In vitro and in vivo suppressive effects of delta-9-tetrahydrocannabinol on interferon production by murine spleen cells . Int J Immunopharmacol 1986; 8 : 819–824. [PubMed] [Google Scholar]
39. Smith SR, Terminelli C, Denhardt G. Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice . J Pharmacol Exp Ther 2000; 293 : 136–150. [PubMed] [Google Scholar]
40. Pellati F, Borgonetti V, Brighenti V, et al. Cannabis sativa L. and nonpsychoactive cannabinoids: their chemistry and role against oxidative stress, inflammation, and cancer . Biomed Res Int 2018; 2018 : 15. [PMC free article] [PubMed] [Google Scholar]
41. Feyer P, Jordan K. Update and new trends in antiemetic therapy: the continuing need for novel therapies . Ann Oncol 2011; 22 : 30–38. [PubMed] [Google Scholar]
42. Grunberg SM, Dugan M, Muss H, et al. Effectiveness of a single-day three-drug regimen of dexamethasone, palonosetron, and aprepitant for the prevention of acute and delayed nausea and vomiting caused by moderately emetogenic chemotherapy . Support Care Cancer 2009; 17 : 589–594. [PubMed] [Google Scholar]
43. Escobar Y, Cajaraville G, Virizuela JA, et al. Incidence of chemotherapy-induced nausea and vomiting with moderately emetogenic chemotherapy: ADVICE (actual data of vomiting incidence by chemotherapy evaluation) study . Support Care Cancer 2015; 23 : 2833–2840. [PMC free article] [PubMed] [Google Scholar]
44. Hsieh RK, Chan A, Kim HK, et al. Baseline patient characteristics, incidence of CINV, and physician perception of CINV incidence following moderately and highly emetogenic chemotherapy in Asia Pacific countries . Supportive Care Cancer 2014; 23 : 263–272. [PubMed] [Google Scholar]
45. Molassiotis A, Farrell C, Bourne K, et al. An exploratory study to clarify the cluster of symptoms predictive of chemotherapy-related nausea using random forest modeling . J Pain Symptom Manage 2012; 44 : 692–703. [PubMed] [Google Scholar]
46. Hickok JT, Roscoe JA, Morrow GR, et al. Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-hydroxytryptamine-3 antiemetics: a University of Rochester James P. Wilmot Cancer Center Community Clinical Oncology Program Study of 360 cancer patients treated in the community . Cancer 2003; 97 : 2880–2886. [PubMed] [Google Scholar]
47. Bloechl-Daum B, Deuson RR, Mavros P, et al. Delayed nausea and vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment . J Clin Oncol 2006; 24 : 4472–4478. [PubMed] [Google Scholar]
48. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the aprepitant protocol 052 study group . J Clin Oncol 2003; 21 : 4112–4119. [PubMed] [Google Scholar]
49. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America . Cancer 2003; 97 : 3090–3098. [PubMed] [Google Scholar]
50. Grunberg SM, Deuson RR, Mavros P, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics . Cancer 2004; 100 : 2261–2268. [PubMed] [Google Scholar]
51. Ballatori E, Roila F, Ruggeri B, et al. The impact of chemotherapy-induced nausea and vomiting on health-related quality of life . Supportive Care Cancer 2007; 15 : 179–185. [PubMed] [Google Scholar]
52. Miller M, Kearney N. Chemotherapy-related nausea and vomiting – past reflections, present practice and future management . Eur J Cancer Care (Engl) 2004; 13 : 71–81. [PubMed] [Google Scholar]
53. Aapro M. Searching for perfection: further progress in management of chemotherapy-induced nausea and vomiting-concluding thoughts . Support Care Cancer 2018; 26 : 35–37. [PMC free article] [PubMed] [Google Scholar]
54. Barann M, Molderings G, Bruss M, et al. Direct inhibition by cannabinoids of human 5-HT3A receptors: probable involvement of an allosteric modulatory site . Br J Pharmacol 2002; 137 : 589–596. [PMC free article] [PubMed] [Google Scholar]
55. Yang KH, Galadari S, Isaev D, et al. The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes . J Pharmacol Exp Ther 2010; 333 : 547–554. [PMC free article] [PubMed] [Google Scholar]
56. Parker LA, Rock EM, Limebeer CL. Regulation of nausea and vomiting by cannabinoids . Br J Pharmacol 2011; 163 : 1411–1422. [PMC free article] [PubMed] [Google Scholar]
57. Van Sickle MD, Duncan M, Kingsley PJ, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors . Science 2005; 310 : 329–332. [PubMed] [Google Scholar]
58. Malik Z, Baik D, Schey R. The role of cannabinoids in regulation of nausea and vomiting, and visceral pain . Curr Gastroenterol Rep 2015; 17 : 429. [PubMed] [Google Scholar]
59. Darmani NA. The cannabinoid CB1 receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55, 212–2 . Eur J Pharmacol 2001; 430 : 49–58. [PubMed] [Google Scholar]
60. Saito R, Takano Y, Kamiya HO. Roles of substance P and NK(1) receptor in the brainstem in the development of emesis . J Pharmacol Sci 2003; 91 : 87–94. [PubMed] [Google Scholar]
61. Tyers MB, Freeman AJ. Mechanism of the anti-emetic activity of 5-HT3 receptor antagonists . Oncology 1992; 49 : 263–268. [PubMed] [Google Scholar]
62. Lever IJ, Malcangio M. CB1 receptor antagonist SR141716A increases capsaicin-evoked release of substance P from the adult mouse spinal cord . Br J Pharmacol 2002; 135 : 21–24. [PMC free article] [PubMed] [Google Scholar]
63. Oshita K, Inoue A, Tang HB, et al. CB1 cannabinoid receptor stimulation modulates transient receptor potential vanilloid receptor 1 activities in calcium influx and substance P release in cultured rat dorsal root ganglion cells . J Pharmacol Sci 2005; 97 : 377–385. [PubMed] [Google Scholar]
64. Mailleux P, Vanderhaeghen JJ. d-9-Tetrahydrocannabinol regulates substance P and enkephalin mRNAs levels in the caudate-putamen . Eur J Pharmacol 1994; 267 : R1–R3. [PubMed] [Google Scholar]
65. Amato L, Davoli M, Minozzi S, et al. Systematic reviews on therapeutic efficacy and safety of Cannabis (including extracts and tinctures) for patients with multiple sclerosis, chronic neuropathic pain, dementia and Tourette syndrome, HIV/AIDS, and cancer receiving chemotherapy . Roma, Italy: Department of Epidemiology Lazio Regional Health Service, 2016. [Google Scholar]
66. Musty RE, Rossi R. Effects of smoked cannabis and oral Δ9-tetrahydrocannabinol on nausea and emesis after cancer chemotherapy: a review of state clinical trials . Journal of Cannabis Therapeutics 2001; 1 : 29–56. [Google Scholar]
67. Smith LA, Azariah F, Lavender VTC, et al. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy . Cochrane Database Syst Rev , 2015; ( 11 ): CD009464. [PMC free article] [PubMed] [Google Scholar]
68. Allan GM, Ramji J, Perry D, et al. Simplified guideline for prescribing medical cannabinoids in primary care . Can Fam Physician 2018; 64 : 111–120. [PMC free article] [PubMed] [Google Scholar]
69. Tennessee So. Evaluation of marijuana and tetrahydrocannabinol in treatment of nausea and/or vomiting associated with cancer therapy unresponsive to conventional anti-emetic therapy: efficacy and toxicity . 1983. [Google Scholar]
70. McNeill RP. (ed.) New Mexico State Legislature . The lynn pierson therapeutic research program: a report on progress to date . Santa Fe: Behavioral health services division, health and environment department, New Mexico State Legislature, 1983. [Google Scholar]
71. Duran M, Perez E, Abanades S, et al. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting . Br J Clin Pharmacol 2010; 70 : 656–663. [PMC free article] [PubMed] [Google Scholar]
72. Meiri D, Jhangiani H, Vredenburgh JJ, et al. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting . Curr Med Res Opin 2007; 23 : 533–543. [PubMed] [Google Scholar]
73. The 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. [Google Scholar]
74. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis . JAMA 2015; 313 : 2456–2473. [PubMed] [Google Scholar]
75. Sorensen CJ, DeSanto K, Borgelt L, et al. Cannabinoid hyperemesis syndrome: diagnosis, pathophysiology, and treatment-a systematic review . J Med Toxicol 2017; 13 : 71–87. [PMC free article] [PubMed] [Google Scholar]
76. Bilkei-Gorzo A, Albayram O, Draffehn A, et al. A chronic low dose of delta(9)-tetrahydrocannabinol (THC) restores cognitive function in old mice . Nat Med 2017; 23 : 782–787. [PubMed] [Google Scholar]
77. Lim M, Kirchof MG. Dermatology-related uses of medical cannabis promoted by dispensaries in Canada, Europe, and the United States . J Cutan Med Surg 2019; 23 : 178–184. [PubMed] [Google Scholar]
78. Tchekmedyian NS, Zahyna D, Halpert C, et al. Clinical aspects of nutrition in advanced cancer . Oncology 1992; 49 ( Suppl. 2 ): 3–7. [PubMed] [Google Scholar]
79. Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients . Supportive Care Cancer 2000; 8 : 175–179. [PubMed] [Google Scholar]
80. Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern cooperative oncology group . Am J Med 1980; 69 : 491–497. [PubMed] [Google Scholar]
81. Watanabe K, Tanaka M, Shimada I, et al. Characterization analysis of loss of appetite among cancer patients and development of a monitoring check sheet corresponding to changes in appetite . International Conference on Food Science and Nutrition 2017; 141–146. [Google Scholar]
82. Stoving RK, Andries A, Brixen K, et al. Leptin, ghrelin, and endocannabinoids: potential therapeutic targets in anorexia nervosa . J Psychiatr Res 2009; 43 : 671–679. [PubMed] [Google Scholar]
83. Kirkham TC, Williams CM, Fezza F, et al. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol . Br J Pharmacol 2002; 136 : 550–557. [PMC free article] [PubMed] [Google Scholar]
84. Williams CM, Kirkham TC. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors . Psychopharmacology 1999; 143 : 315–317. [PubMed] [Google Scholar]
85. Williams CM, Kirkham TC. Observational analysis of feeding induced by D9-THC and anandamide . Physiol Behav 2002; 76 : 241–250. [PubMed] [Google Scholar]
86. Ravinet Trillou C, Arnone M, delgorge C, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice . Am J Physiol Regul Integr Comp Physiol 2002; 284 : R345–R353. [PubMed] [Google Scholar]
87. Koch JE. D9-THC stimulates food intake in Lewis rats: effects on chow, high-fat and sweet high-fat diets . Pharmacol Biochem Behav 2001; 68 : 539–543. [PubMed] [Google Scholar]
88. Koch M, Varela L, Kim JG, et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding . Nature 2015; 519 : 45–50. [PMC free article] [PubMed] [Google Scholar]
89. Williams CM, Rogers PJ, Kirkham TC. Hyperphagia in pre-fed rats following oral D9-THC . Physiol Behav 1998; 65 : 343–346. [PubMed] [Google Scholar]
90. Nelson K, Walsh D, Deeter P, et al. A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia . J Palliat Care 1994; 10 : 14–18. [PubMed] [Google Scholar]
91. Riggs PK, Vaida F, Rossi SS, et al. A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men . Brain Res 2012; 1431 : 46–52. [PMC free article] [PubMed] [Google Scholar]
92. Bar-Lev Schleider L, Mechoulam R, Lederman V, et al. Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer . Eur J Intern Med 2018; 49 : 37–43. [PubMed] [Google Scholar]
93. Jatoi A. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central cancer treatment group study . J Clin Oncol 2002; 20 : 567–573. [PubMed] [Google Scholar]
94. Strasser F, Luftner D, Possinger K, et al. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the cannabis-in-cachexia-study-group . J Clin Oncol 2006; 24 : 3394–3400. [PubMed] [Google Scholar]
95. Brisbois TD, de Kock IH, Watanabe SM, et al. Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial . Ann Oncol 2011; 22 : 2086–2093. [PubMed] [Google Scholar]
96. Abrams DI, Hilton JF, Leiser RJ, et al. Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial . Ann Intern Med 2003; 139 : 258–266. [PubMed] [Google Scholar]
97. Haney M, Rabkin J, Gunderson E, et al. Dronabinol and marijuana in HIV(+) marijuana smokers: acute effects on caloric intake and mood . Psychopharmacology (Berl) 2005; 181 : 170–178. [PubMed] [Google Scholar]
98. Haney M, Gunderson E, Rabkin J, et al. Dronabinol and marijuana in HIV-positive marijuana smokers: caloric intake, mood, and sleep . J Acquir Immune Defic Syndr 2007; 45 : 545–554. [PubMed] [Google Scholar]
99. Volicer L, Stelly M, Morris J, et al. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease . Int J Geriatr Psychiatry 1997; 12 : 913–919. [PubMed] [Google Scholar]
100. van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years . Ann Oncol 2007; 18 : 1437–1449. [PubMed] [Google Scholar]
101. Reis AD, Pereira P, Diniz RR, et al. Effect of exercise on pain and functional capacity in breast cancer patients . Health Qual Life Outcomes 2018; 16 : 58. [PMC free article] [PubMed] [Google Scholar]
102. McNeely ML, Parliament MB, Seikaly H, et al. Effect of exercise on upper extremity pain and dysfunction in head and neck cancer survivors: a randomized controlled trial . Cancer 2008; 113 : 214–222. [PubMed] [Google Scholar]
103. Galiano-Castillo N, Cantarero-Villanueva I, Fernandez-Lao C, et al. Telehealth system: a randomized controlled trial evaluating the impact of an internet-based exercise intervention on quality of life, pain, muscle strength, and fatigue in breast cancer survivors . Cancer 2016; 122 : 3166–3174. [PubMed] [Google Scholar]
104. Kleckner IR, Dunne RF, Asare M, et al. Exercise for toxicity management in cancer—a narrative review . Oncol Hematol Rev 2018; 14 : 28–37. [PMC free article] [PubMed] [Google Scholar]
105. Syrjala KL, Jensen MP, Mendoza ME, et al. Psychological and behavioral approaches to cancer pain management . J Clin Oncol 2014; 32 : 1703–1711. [PMC free article] [PubMed] [Google Scholar]
106. Kwekkeboom KL, Cherwin CH, Lee JW, et al. Mind-body treatments for the pain-fatigue-sleep disturbance symptom cluster in persons with cancer . J Pain Symptom Manage 2010; 39 : 126–138. [PMC free article] [PubMed] [Google Scholar]
107. Money S, Garber B. Management of cancer pain . Curr Emerg Hosp Med Rep 2018; 6 : 141–146. [Google Scholar]
108. Schmidt BL, Hamamoto DT, Simone DA, et al. Mechanisms of cancer pain . Mol Interv 2010; 10 : 164–178. [PMC free article] [PubMed] [Google Scholar]
109. Sherif MA, Cortes-Briones JA, Ranganathan M, et al. Cannabinoid-glutamate interactions and neural oscillations: implications for psychosis . Eur J Neurosci 2018; 48 : 2890–2902. [PubMed] [Google Scholar]
110. Nielsen S, Sabioni P, Trigo JM, et al. Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis . Neuropsychopharmacology 2017; 42 : 1752–1765. [PMC free article] [PubMed] [Google Scholar]
111. Kehl LJ, Hamamoto DT, Wacnik PW, et al. A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain . Pain 2003; 103 : 175–186. [PubMed] [Google Scholar]
112. Guerrero AV, Quang P, Dekker N, et al. Peripheral cannabinoids attenuate carcinoma-induced nociception in mice . Neurosci Lett 2008; 433 : 77–81. [PMC free article] [PubMed] [Google Scholar]
113. Blake A, Wan BA, Malek L, et al. A selective review of medical cannabis in cancer pain management . Ann Palliat Med 2017; 6 : S215-S222. [PubMed] [Google Scholar]
114. Bennett M, Paice JA, Wallace M. Pain and opioids in cancer care: benefits, risks, and alternatives . Am Soc Clin Oncol Educ Book 2017; 37 : 705–713. [PubMed] [Google Scholar]
115. Fallon MT, Albert Lux E, McQuade R, et al. Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies . Br J Pain 2017; 11 : 119–133. [PMC free article] [PubMed] [Google Scholar]
116. Lynch ME, Ware MA. Cannabinoids for the treatment of chronic non-cancer pain: an updated systematic review of randomized controlled trials . J Neuroimmune Pharmacol 2015; 10 : 293–301. [PubMed] [Google Scholar]
117. Light MK, Orens A, Lewandowski B, et al. Market size and demand for marijuana in Colorado . In: The Marijuana Policy Group (ed.) Colorado Department of Revenue, 2014. [Google Scholar]
118. Ilgen MA, Bohnert K, Kleinberg F, et al. Characteristics of adults seeking medical marijuana certification . Drug Alcohol Depend 2013; 132 : 654–659. [PubMed] [Google Scholar]
119. Pergam SA, Woodfield MC, Lee CM, et al. Cannabis use among patients at a comprehensive cancer center in a state with legalized medicinal and recreational use . Cancer 2017; 123 : 4488–4497. [PMC free article] [PubMed] [Google Scholar]
120. Poli P, Crestani F, Salvadori C, et al. Medicinal cannabis in patients with chronic pain: effect on pain-relief, pain disability, and psychological aspects. A prospective non randomized single arm clinical trial . Clin Ter 2018; 169 : e102–e107. [PubMed] [Google Scholar]
121. Scavone JL, Sterling RC, Van Bockstaele EJ. Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal . Neuroscience 2013; 248 : 637–654. [PMC free article] [PubMed] [Google Scholar]
122. Cox ML, Haller VL, Welch SP. Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat . Eur J Pharmacol 2007; 567 : 125–130. [PubMed] [Google Scholar]
123. Hosking RD, Zajicek JP. Therapeutic potential of cannabis in pain medicine . Br J Anaesth 2008; 101 : 59–68. [PubMed] [Google Scholar]
124. Abrams DI, Couey P, Shade SB, et al. Cannabinoid-opioid interaction in chronic pain . Clin Pharmacol Ther 2011; 90 : 844–851. [PubMed] [Google Scholar]
125. Boehnke KF, Litinas E, Clauw DJ. Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain . J Pain 2016; 17 : 739–744. [PubMed] [Google Scholar]
126. Reiman A, Welty M, Solomon P. Cannabis as a substitute for opioid-based pain medication: patient self-report . Cannabis Cannabinoid Res 2017; 2 : 160–166. [PMC free article] [PubMed] [Google Scholar]
127. Johnson JR, Burnell-Nugent M, Lossignol D, et al. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain . J Pain Symptom Manage 2010; 39 : 167–179. [PubMed] [Google Scholar]
128. Bradford AC, Bradford WD. Medical marijuana laws reduce prescription medication use in Medicare Part D . Health Aff (Millwood) 2016; 35 : 1230–1236. [PubMed] [Google Scholar]
129. Bachhuber MA, Saloner B, Cunningham CO, et al. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999–2010 . JAMA Intern Med 2014; 174 : 1668–1673. [PMC free article] [PubMed] [Google Scholar]
130. Vergara D, Bidwell LC, Gaudino R, et al. Compromised external validity: federally produced cannabis does not reflect legal markets . Sci Rep 2017; 7 : 46528. [PMC free article] [PubMed] [Google Scholar]
131. Fehrenbacher JC. Chemotherapy-induced peripheral neuropathy . Prog Mol Biol Transl Sci 2015; 131 : 471–508. [PubMed] [Google Scholar]
132. Seretny M, Currie GL, Sena ES, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis . Pain 2014; 155 : 2461–2470. [PubMed] [Google Scholar]
133. Ewertz M, Qvortrup C, Eckhoff L. Chemotherapy-induced peripheral neuropathy in patients treated with taxanes and platinum derivatives . Acta Oncol 2015; 54 : 587–591. [PubMed] [Google Scholar]
134. Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy . Pain 2002; 98 : 195–203. [PubMed] [Google Scholar]
135. Mitchell PL, Goldstein D, Michael M, et al. Addition of gabapentin to a modified FOLFOX regimen does not reduce oxaliplatin-induced neurotoxicity . Clin Colorectal Cancer 2006; 6 : 146–151. [PubMed] [Google Scholar]
136. Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy . Cancer 2008; 112 : 2802–2808. [PubMed] [Google Scholar]
137. Pascual D, Goicoechea C, Suardiaz M, et al. A cannabinoid agonist, WIN 55,212–2, reduces neuropathic nociception induced by paclitaxel in rats . Pain 2005; 118 : 23–34. [PubMed] [Google Scholar]
138. Rahn EJ, Makriyannis A, Hohmann AG. Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats . Br J Pharmacol 2007; 152 : 765–777. [PMC free article] [PubMed] [Google Scholar]
139. Rahn EJ, Zvonok AM, Thakur GA, et al. Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats . J Pharmacol Exp Ther 2008; 327 : 584–591. [PMC free article] [PubMed] [Google Scholar]
140. Deng L, Guindon J, Vemuri VK, et al. The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB(2) receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy . Mol Pain 2012; 8 : 71. [PMC free article] [PubMed] [Google Scholar]
141. Ward SJ, Ramirez MD, Neelakantan H, et al. Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female C57Bl6 mice . Anesth Analg 2011; 113 : 947–950. [PMC free article] [PubMed] [Google Scholar]
142. Ward SJ, McAllister SD, Kawamura R, et al. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy . Br J Pharmacol 2014; 171 : 636–645. [PMC free article] [PubMed] [Google Scholar]
143. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain . J Pain 2008; 9 : 506–521. [PMC free article] [PubMed] [Google Scholar]
144. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial . Neurology 2007; 68 : 515–521. [PubMed] [Google Scholar]
145. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial . Neuropsychopharmacology 2009; 34 : 672–680. [PMC free article] [PubMed] [Google Scholar]
146. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial . CMAJ 2010; 182 : E694–E701. [PMC free article] [PubMed] [Google Scholar]
147. Wilsey B, Marcotte T, Deutsch R, et al. Low-dose vaporized cannabis significantly improves neuropathic pain . J Pain 2013; 14 : 136–148. [PMC free article] [PubMed] [Google Scholar]
148. Hoggart B, Ratcliffe S, Ehler E, et al. A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain . J Neurol 2015; 262 : 27–40. [PubMed] [Google Scholar]
149. Xie J, Xiao D, Xu Y, et al. Up-regulation of immunomodulatory effects of mouse bone-marrow derived mesenchymal stem cells by tetrahydrocannabinol pre-treatment involving cannabinoid receptor CB2 . Oncotarget 2016; 7 : 6436–6447. [PMC free article] [PubMed] [Google Scholar]
150. King KM, Myers AM, Soroka-Monzo AJ, et al. Single and combined effects of delta(9) -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain . Br J Pharmacol 2017; 174 : 2832–2841. [PMC free article] [PubMed] [Google Scholar]
151. McQuade RM, Stojanovska V, Abalo R, et al. Chemotherapy-induced constipation and diarrhea: pathophysiology, current and emerging treatments . Front Pharmacol 2016; 7 : 414. [PMC free article] [PubMed] [Google Scholar]
152. Zhang LR, Morgenstern H, Greenland S, et al. Cannabis smoking and lung cancer risk: pooled analysis in the international lung cancer consortium . Int J Cancer 2015; 136 : 894–903. [PMC free article] [PubMed] [Google Scholar]
153. Tarricone R, Abu Koush D, Nyanzi-Wakholi B, et al. A systematic literature review of the economic implications of chemotherapy-induced diarrhea and its impact on quality of life . Crit Rev Oncol Hematol 2016; 99 : 37–48. [PubMed] [Google Scholar]
154. Pouncey AL, Scott AJ, Alexander JL, et al. Gut microbiota, chemotherapy and the host: the influence of the gut microbiota on cancer treatment . Ecancermedicalscience 2018; 12 : 868. [PMC free article] [PubMed] [Google Scholar]
155. Pagano E, Capasso R, Piscitelli F, et al. An orally active cannabis extract with high content in cannabidiol attenuates chemically-induced intestinal inflammation and hypermotility in the mouse . Front Pharmacol 2016; 7 : 341. [PMC free article] [PubMed] [Google Scholar]
156. Goyal H, Singla U, Gupta U, et al. Role of cannabis in digestive disorders . Eur J Gastroenterol Hepatol 2017; 29 : 135–143. [PubMed] [Google Scholar]
157. Sharkey KA, Wiley JW. The role of the endocannabinoid system in the brain-gut axis . Gastroenterology 2016; 151 : 252–266. [PMC free article] [PubMed] [Google Scholar]
158. Borrelli F, Aviello G, Romano B, et al. Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant cannabis sativa, is protective in a murine model of colitis . J Mol Med (Berl) 2009; 87 : 1111–1121. [PubMed] [Google Scholar]
159. Zuardi AW. History of cannabis as a medicine: a review . Rev Bras Psiquiatr 2006; 28 : 153–157. [PubMed] [Google Scholar]
160. Weiss A, Friedenberg F. Patterns of cannabis use in patients with inflammatory bowel disease: a population based analysis . Drug Alcohol Depend 2015; 156 : 84–89. [PubMed] [Google Scholar]
161. Lal S, Prasad N, Ryan M, et al. Cannabis use amongst patients with inflammatory bowel disease . Eur J Gastroenterol Hepatol 2011; 23 : 891–896. [PubMed] [Google Scholar]
162. Storr M, Devlin S, Kaplan GG, et al. Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn’s disease . Inflamm Bowel Dis 2014; 20 : 472–480. [PubMed] [Google Scholar]
163. Hoffenberg EJ, McWilliams SK, Mikulich-Gilbertson SK, et al. Marijuana use by adolescents and young adults with inflammatory bowel disease . J Pediatr 2018; 199 : 99–105. [PubMed] [Google Scholar]
164. Phatak UP, Rojas-Velasquez D, Porto A, et al. Prevalence and patterns of marijuana use in young adults with inflammatory bowel disease . J Pediatr Gastroenterol Nutr 2017; 64 : 261–264. [PubMed] [Google Scholar]
165. Merker AM, Riaz M, Friedman S, et al. Legalization of medicinal marijuana has minimal impact on use patterns in patients with inflammatory bowel disease . Inflamm Bowel Dis 2018; 24 : 2309–2314. [PubMed] [Google Scholar]
166. Ahmed W, Katz S. Therapeutic use of Cannabis in inflammatory bowel disease . Gastroenterol Hepatol (N Y) 2016; 12 : 668–679. [PMC free article] [PubMed] [Google Scholar]
167. Janelsins MC, Heckler CE, Peppone LJ, et al. Longitudinal trajectory and characterization of cancer-related cognitive impairment in a nationwide cohort study . J Clin Oncol 2017; 35 : 506–514. [PMC free article] [PubMed] [Google Scholar]
168. Hardy SJ, Krull KR, Wefel JS, et al. Cognitive changes in cancer survivors . ASCO Educational Book; https://asco.org/edbook, 2018. [PubMed] [Google Scholar]
169. Wefel JS, Kesler SR, Noll KR, et al. Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults . CA Cancer J Clin 2015; 65 : 123–138. [PMC free article] [PubMed] [Google Scholar]
170. McDonald BC, Conroy SK, Ahles TA, et al. Alterations in brain activation during working memory processing associated with breast cancer and treatment: a prospective functional magnetic resonance imaging study . J Clin Oncol 2012; 30 : 2500–2508. [PMC free article] [PubMed] [Google Scholar]
171. Zhou W, Kavelaars A, Heijnen CJ. Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice . PLoS One 2016; 11 : e0151890. [PMC free article] [PubMed] [Google Scholar]
172. Von Ah D, Jansen CE, Allen DH. Evidence-based interventions for cancer- and treatment-related cognitive impairment . Clin J Oncol Nurs 2014; 18 ( Suppl. ): 17–25. [PubMed] [Google Scholar]
173. Kohli S, Fisher SG, Tra Y, et al. The effect of modafinil on cognitive function in breast cancer survivors . Cancer 2009; 115 : 2605–2616. [PMC free article] [PubMed] [Google Scholar]
174. Lundorff LE, Jonsson BH, Sjogren P. Modafinil for attentional and psychomotor dysfunction in advanced cancer: a double-blind, randomised, cross-over trial . Palliat Med 2009; 23 : 731–738. [PubMed] [Google Scholar]
175. Gehring K, Patwardhan SY, Collins R, et al. A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor . J Neurooncol 2012; 107 : 165–174. [PubMed] [Google Scholar]
176. Mar Fan HG, Clemons M, Xu W, et al. A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer . Support Care Cancer 2008; 16 : 577–583. [PubMed] [Google Scholar]
177. Osborne AL, Solowij N, Weston-Green K. A systematic review of the effect of cannabidiol on cognitive function: relevance to schizophrenia . Neurosci Biobehav Rev 2017; 272 : 310–324. [PubMed] [Google Scholar]
178. Cohen K, Weinstein A. The effects of cannabinoids on executive functions: evidence from cannabis and synthetic cannabinoids-a systematic review . Brain Sci 2018; 8 : pii: E40. [PMC free article] [PubMed] [Google Scholar]
179. Schreiner AM, Dunn ME. Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis . Exp Clin Psychopharmacol 2012; 20 : 420–429. [PubMed] [Google Scholar]
180. Sarne Y, Toledano R, Rachmany L, et al. Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol . Neurobiol Aging 2018; 61 : 177–186. [PubMed] [Google Scholar]
181. da Silva VK, de Freitas BS, Dornelles VC, et al. Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: reversal by cannabidiol . Brain Res Bull 2018; 139 : 1–8. [PubMed] [Google Scholar]
182. Schiavon AP, Soares LM, Bonato JM, et al. Protective effects of cannabidiol against hippocampal cell death and cognitive impairment induced by bilateral common carotid artery occlusion in mice . Neurotox Res 2014; 26 : 307–316. [PubMed] [Google Scholar]
183. Cheng D, Low JK, Logge W, et al. Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1E9 mice . Psychopharmacology (Berl) 2014; 231 : 3009–3017. [PubMed] [Google Scholar]
184. Aso E, Sanchez-Pla A, Vegas-Lozano E, et al. Cannabis-based medicine reduces multiple pathological processes in AbetaPP/PS1 mice . J Alzheimers Dis 2015; 43 : 977–991. [PubMed] [Google Scholar]
185. Jouroukhin Y, Zhu X, Shevelkin AV, et al. Adolescent delta(9)-tetrahydrocannabinol exposure and astrocyte-specific genetic vulnerability converge on nuclear factor-kappab-cyclooxygenase-2 signaling to impair memory in adulthood . Biol Psychiatry 2019; 85 : 891–903. [PMC free article] [PubMed] [Google Scholar]
186. Myers AM, Siegele PB, Foss JD, et al. Single and combined effects of plant-derived and synthetic cannabinoids on cognition and cannabinoid-associated withdrawal signs in mice . Br J Pharmacol 2019; 176 : 1552–1567. [PMC free article] [PubMed] [Google Scholar]
187. Murphy M, Mills S, Winstone J, et al. Chronic adolescent delta(9)-tetrahydrocannabinol treatment of male mice leads to long-term cognitive and behavioral dysfunction, which are prevented by concurrent cannabidiol treatment . Cannabis Cannabinoid Res 2017; 2 : 235–246. [PMC free article] [PubMed] [Google Scholar]
188. Vargish GA, McBain CJ. The hyperpolarization-activated cation current Ih: the missing link connecting cannabinoids to cognition . Neuron 2016; 89 : 889–891. [PubMed] [Google Scholar]
189. Maroso M, Szabo GG, Kim HK, et al. Cannabinoid control of learning and memory through HCN channels . Neuron 2016; 89 : 1059–1073. [PMC free article] [PubMed] [Google Scholar]
190. Bar-Sela G, Vorobeichik M, Drawsheh S, et al. The medical necessity for medicinal cannabis: prospective, observational study evaluating the treatment in cancer patients on supportive or palliative care . Evid Based Complement Alternat Med 2013; 2013 : 510392. [PMC free article] [PubMed] [Google Scholar]
191. Bar-Sela G, Tauber D, Mitnik I, et al. Cannabis-related cognitive impairment: a prospective evaluation of possible influences on patients with cancer during chemotherapy treatment as a pilot study . Anticancer Drugs 2019; 30 : 91–97. [PubMed] [Google Scholar]
192. Lyketsos CG, Garrett E, Liang KY, et al. Cannabis use and cognitive decline in persons under 65 years of age . Am J Epidemiol 1999; 149 : 794–800. [PubMed] [Google Scholar]
193. Solowij N, Stephens RS, Roffman RA, et al. Cognitive functioning of long-term heavy cannabis users seeking treatment . JAMA 2002; 287 : 1123–1131. [PubMed] [Google Scholar]
194. Broyd SJ, van Hell HH, Beale C, et al. Acute and chronic effects of cannabinoids on human cognition-a systematic review . Biol Psychiatry 2016; 79 : 557–567. [PubMed] [Google Scholar]
195. Gilman JM, Kuster JK, Lee S, et al. Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users . J Neurosci 2014; 2014 ; 34 : 5529–5538. [PMC free article] [PubMed] [Google Scholar]
196. Stark DPH, House A. Anxiety in cancer patients . Br J Cancer 2000; 83 : 1261–1287. [PMC free article] [PubMed] [Google Scholar]
197. Young K, Singh G. Biological mechanisms of cancer-induced depression . Front Psychiatry 2018; 9 : 299. [PMC free article] [PubMed] [Google Scholar]
198. Howell D, Olsen K. Distress—the 6th vital sign . Curr Oncol 2011; 18 : 208–210. [PMC free article] [PubMed] [Google Scholar]
199. Carlson LE, Bultz BD. Cancer distress screening . J Psychosom Res 2003; 55 : 403–409. [PubMed] [Google Scholar]
200. Bates GE, Mostel JL, Hesdorffer M. Cancer-related anxiety . JAMA Oncol 2017; 3 : 1007. [PubMed] [Google Scholar]
201. Micale V, Di Marzo V, Sulcova A, et al. Endocannabinoid system and mood disorders: priming a target for new therapies . Pharmacol Ther 2013; 138 : 18–37. [PubMed] [Google Scholar]
202. Valverde O, Torrens M. CB1 receptor-deficient mice as a model for depression . Neuroscience 2012; 204 : 193–206. [PubMed] [Google Scholar]
203. Blessing EM, Steenkamp MM, Manzanares J, et al. Cannabidiol as a potential treatment for anxiety disorders . Neurotherapeutics 2015; 12 : 825–836. [PMC free article] [PubMed] [Google Scholar]
204. Campos AC, Ortega Z, Palazuelos J, et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system . Int J Neuropsychopharmacol 2013; 16 : 1407–1419. [PubMed] [Google Scholar]
205. Fogaca MV, Campos AC, Coelho LD, et al. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: role of neurogenesis and dendritic remodeling . Neuropharmacology 2018; 135 : 22–33. [PubMed] [Google Scholar]
206. Rock EM, Limebeer CL, Petrie GN, et al. Effect of prior foot shock stress and delta(9)-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats . Psychopharmacology (Berl) 2017; 234 : 2207–2217. [PubMed] [Google Scholar]
207. Corroon J, Phillips JA. A cross-sectional study of cannabidiol users . Cannabis Cannabinoid Res 2018; 3 : 152–161. [PMC free article] [PubMed] [Google Scholar]
208. Swift W, Gates P, Dillon P. Survey of Australians using cannabis for medical purposes . Harm Reduct J 2005; 2 : 18. [PMC free article] [PubMed] [Google Scholar]
209. Waissengrin B, Urban D, Leshem Y, et al. Patterns of use of medical cannabis among Israeli cancer patients: a single institution experience . J Pain Symptom Manage 2015; 49 : 223–230. [PubMed] [Google Scholar]
210. Jadoon KA, Ratcliffe SH, Barrett DA, et al. Efficacy and safety of cannabidiol and tetrahydrocannabivarin on glycemic and lipid parameters in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel group pilot study . Diabetes Care 2016; 39 : 1–10. [PubMed] [Google Scholar]
211. Degenhardt L, Hall W, Lynskey M. Exploring the association between cannabis use and depression . Addiction 2003; 98 : 1493–1504. [PubMed] [Google Scholar]
212. Mammen G, Rueda S, Roerecke M, et al. Association of cannabis with long-term clinical symptoms in anxiety and mood disorders: a systematic review of prospective studies . J Clin Psychiatry 2018; 79 : pii: 17r11839. [PubMed] [Google Scholar]
213. Hayatbakhsh MR, Najman JM, Jamrozik K, et al. Cannabis and anxiety and depression in young adults: a large prospective study . J Am Acad Child Adolesc Psychiatry 2007; 46 : 408–417. [PubMed] [Google Scholar]
214. Lev-Ran S, Roerecke M, Le Foll B, et al. The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies . Psychol Med 2014; 44 : 797–810. [PubMed] [Google Scholar]
215. Twomey CD. Association of cannabis use with the development of elevated anxiety symptoms in the general population: a meta-analysis . J Epidemiol Community Health 2017; 71 : 811–816. [PubMed] [Google Scholar]
216. Denson TF, Earleywine M. Decreased depression in marijuana users . Addict Behav 2006; 31 : 738–742. [PubMed] [Google Scholar]
217. Zuardi AW, Shirakawa I, Finkelfarb E, et al. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects . Psychopharmacology 1982; 76 : 245–250. [PubMed] [Google Scholar]
218. Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology . Neuropsychopharmacology 2010; 35 : 764–774. [PMC free article] [PubMed] [Google Scholar]
219. Englund A, Atakan Z, Kralj A, et al. The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: a placebo-controlled, double-blind, crossover pilot trial . J Psychopharmacol 2016; 30 : 140–151. [PubMed] [Google Scholar]
220. Gelfand EV, Cannon CP. Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple cardiometabolic risk factors . J Am Coll Cardiol 2006; 47 : 1919–1926. [PubMed] [Google Scholar]
221. Topol EJ, Bousser MG, Fox KAA, et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial . Lancet 2010; 376 : 517–523. [PubMed] [Google Scholar]
222. Christensen R, Kristensen PK, Bartels EM, et al. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials . Lancet 2007; 370 : 1706–1713. [PubMed] [Google Scholar]
223. Palesh OG, Roscoe JA, Mustian KM, et al. Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester cancer center-community clinical oncology program . J Clin Oncol 2010; 28 : 292–298. [PMC free article] [PubMed] [Google Scholar]
224. Palesh O, Aldridge-Gerry A, Ulusakarya A, et al. Sleep disruption in breast cancer patients and survivors . JNCCN 2013; 11 : 1523–1530. [PubMed] [Google Scholar]
225. Mustian KM, Alfano CM, Heckler C, et al. Comparison of pharmaceutical, psychological, and exercise treatments for cancer-related fatigue: a meta-analysis . JAMA Oncol 2017; 3 : 961–968. [PMC free article] [PubMed] [Google Scholar]
226. Prospero-Garcia O, Amancio-Belmont O, Becerril Melendez AL, et al. Endocannabinoids and sleep . Neurosci Biobehav Rev 2016; 71 : 671–679. [PubMed] [Google Scholar]
227. Martinez-Vargas M, Morales-Gomez J, Gonzalez-Rivera R, et al. Does the neuroprotective role of anandamide display diurnal variations? Int J Mol Sci 2013; 14 : 23341–23355. [PMC free article] [PubMed] [Google Scholar]
228. Hanlon EC, Tasali E, Leproult R, et al. Circadian rhythm of circulating levels of the endocannabinoid 2-arachidonoylglycerol . J Clin Endocrinol Metab 2015; 100 : 220–226. [PMC free article] [PubMed] [Google Scholar]
229. Russo E, Guy GW, Robson PJ. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of sativex, a cannabis-based medicine . Chem Biodivers 2007; 4 : 1729–1743. [PubMed] [Google Scholar]
230. Babson KA, Sottile J, Morabito D. Cannabis, cannabinoids, and sleep: a review of the literature . Curr Psychiatry Rep 2017; 19 : 23. [PubMed] [Google Scholar]
231. Hergenrather J. Cannabis alleviates symptoms of Crohn’s disease . O’Shaughnessy’s Autumn, 2005. [Google Scholar]
232. Kindred JH, Li K, Ketelhut NB, et al. Cannabis use in people with Parkinson’s disease and multiple sclerosis: a web-based investigation . Complement Ther Med 2017; 33 : 99–104. [PubMed] [Google Scholar]
233. Bonn-Miller MO, Babson KA, Vandrey R. Using cannabis to help you sleep: heightened frequency of medical cannabis use among those with PTSD . Drug Alcohol Depend 2014; 136 : 162–165. [PMC free article] [PubMed] [Google Scholar]
234. Zettl UK, Rommer P, Hipp P, et al. Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis . Ther Adv Neurol Disord 2016; 9 : 9–30. [PMC free article] [PubMed] [Google Scholar]
236. Dieli-Conwright CM, Wong L, Waliany S, et al. An observational study to examine changes in metabolic syndrome components in patients with breast cancer receiving neoadjuvant or adjuvant chemotherapy . Cancer 2016; 122 : 2646–2653. [PMC free article] [PubMed] [Google Scholar]
237. Grossman M, Hamilton EJ, Gilfillan C, et al. Bone and metabolic health in patients with non-metastatic prostate cancer who are receiving androgen deprivation therapy . Med J Aust 2011; 194 : 301–306. [PubMed] [Google Scholar]
238. Rezkalla S, Kloner RA. Cardiovascular effects of marijuana . Trends Cardiovasc Med . Epub ahead of print 10 November 2018. DOI: 10.1016/j.tcm.2018.11.004. [PubMed] [CrossRef]
239. Sierra S, Luquin N, Navarro-Otano J. The endocannabinoid system in cardiovascular function: novel insights and clinical implications . Clin Auton Res 2018; 28 : 35–52. [PubMed] [Google Scholar]
240. Hebert-Chatelain E, Desprez T, Serrat R, et al. A cannabinoid link between mitochondria and memory . Nature 2016; 539 : 555–559. [PubMed] [Google Scholar]
241. Ofek O, Karsak M, Leclerc N, et al. Peripheral cannabinoid receptor, CB2, regulates bone mass . Proc Natl Acad Sci USA 2006; 103 : 696–701. [PMC free article] [PubMed] [Google Scholar]
242. Hao E, Mukhopadhyay P, Cao Z, et al. Cannabidiol protects against doxorubicin-induced cardiomyopathy by modulating mitochondrial function and biogenesis . Mol Med 2015; 21 : 38–45. [PMC free article] [PubMed] [Google Scholar]
243. Alpert JS. Marijuana for diabetic control . Am J Med 2013; 126 : 557–558. [PubMed] [Google Scholar]
244. Alshaarawy O, Anthony JC. Cannabis smoking and diabetes mellitus: results from meta-analysis with eight independent replication samples . Epidemiology 2015; 26 : 597–600. [PMC free article] [PubMed] [Google Scholar]
245. Muniyappa R, Sable S, Ouwerkerk R, et al. Metabolic effects of chronic cannabis smoking . Diabetes Care 2013; 36 : 2415–2422. [PMC free article] [PubMed] [Google Scholar]
246. Reuter SE, Martin JH. Pharmacokinetics of cannabis in cancer cachexia-anorexia syndrome . Clin Pharmacokinet 2016; 55 : 807–812. [PubMed] [Google Scholar]
247. Gowran A, McKayed K, Campbell VA. The cannabinoid receptor type 1 is essential for mesenchymal stem cell survival and differentiation: implications for bone health . Stem Cells Int 2013; 2013 : 796715. [PMC free article] [PubMed] [Google Scholar]
248. Lozano-Ondoua AN, Hanlon KE, Symons-Liguori AM, et al. Disease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists . J Bone Miner Res 2013; 28 : 92–107. [PMC free article] [PubMed] [Google Scholar]
249. Lozano-Ondoua AN, Wright C, Vardanyan A, et al. A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss . Life Sci 2010; 86 : 646–653. [PMC free article] [PubMed] [Google Scholar]
250. Hall W, Solowij N. Adverse effects of cannabis . Lancet 1998; 352 : 1611–1616. [PubMed] [Google Scholar]
251. Huestis MA. Cannabis (marijuana) – Effects on human behavior and performance . Forensic Sci Rev 2002; 14 ( 1–2 ): 15–60. [PubMed] [Google Scholar]
252. Ramaekers JG, Berghaus G, van Laar M, et al. Dose related risk of motor vehicle crashes after cannabis use . Drug Alcohol Depend 2004; 73 : 109–119. [PubMed] [Google Scholar]
253. Volkow ND, Baler RD, Compton WM, et al. Adverse health effects of marijuana use . N Engl J Med 2014; 370 : 2219–2227. [PMC free article] [PubMed] [Google Scholar]
254. Zuardi AW, Rodrigues JA, Cunha JM. Effects of cannabidiol in animal models predictive of antipsychotic activity . Psychopharmacology 1991; 104 : 260–264. [PubMed] [Google Scholar]
255. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the dravet syndrome . N Engl J Med 2017; 376 : 2011–2020. [PubMed] [Google Scholar]
256. Kalant H. Adverse effects of cannabis on health: an update of the literature since 1996 . Prog Neuropsychopharmacol Biol Psychiatry 2004; 28 : 849–863. [PubMed] [Google Scholar]
257. Decuyper II, Van Gasse AL, Cop N, et al. Cannabis sativa allergy: looking through the fog . Allergy 2017; 72 : 201–206. [PubMed] [Google Scholar]
258. Wolff V, Schlagowski AI, Rouyer O, et al. Tetrahydrocannabinol induces brain mitochondrial respiratory chain dysfunction and increases oxidative stress: a potential mechanism involved in cannabis-related stroke . Biomed Res Int 2015; 2015 : 323706. [PMC free article] [PubMed] [Google Scholar]
259. Hall W. What has research over the past two decades revealed about the adverse health effects of recreational cannabis use? Addiction 2015; 110 : 19–35. [PubMed] [Google Scholar]
260. Pacher P, Steffens S, Hasko G, et al. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly . Nat Rev Cardiol 2018; 15 : 151–166. [PubMed] [Google Scholar]
261. Gage SH, Jones HJ, Burgess S, et al. Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study . Psychol Med 2017; 47 : 971–980. [PMC free article] [PubMed] [Google Scholar]
262. Sophocleous A, Robertson R, Ferreira NB, et al. Heavy cannabis use is associated with low bone mineral density and an increased risk of fractures . Am J Med 2017; 130 : 214–221. [PubMed] [Google Scholar]
263. Bolla KI, Lesage SR, Gamaldo CE, et al. Sleep disturbance in heavy marijuana users . Sleep 2008; 31 : 901–908. [PMC free article] [PubMed] [Google Scholar]
264. Alzghari SK, Fung V, Rickner SS, et al. To dab or not to dab: rising concerns regarding the toxicity of cannabis concentrates . Cureus 2017; 9 : e1676. [PMC free article] [PubMed] [Google Scholar]
265. Argamany JR, Reveles KR, Duhon B. Synthetic cannabinoid hyperemesis resulting in rhabdomyolysis and acute renal failure . Am J Emerg Med 2016; 34 : 765 e1–e2. [PubMed] [Google Scholar]
266. McLaren J, Swift W, Dillon P, et al. Cannabis potency and contamination: a review of the literature . Addiction 2008; 103 : 1100–1109. [PubMed] [Google Scholar]
267. Dryburgh LM, Bolan NS, Grof CPL, et al. Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects . Br J Clin Pharmacol 2018; 84 : 2468–2476. [PMC free article] [PubMed] [Google Scholar]
268. Hecht SS. Tobacco carcinogens, their biomarkers and tobacco-induced cancer . Nat Rev Cancer 2003; 3 : 733–744. [PubMed] [Google Scholar]
269. Smyth EC, Capanu M, Janjigian YY, et al. Tobacco use is associated with increased recurrence and death from gastric cancer . Ann Surg Oncol 2012; 19 : 2088–2094. [PubMed] [Google Scholar]
270. Ramamoorthy S, Luo L, Luo E, et al. Tobacco smoking and risk of recurrence for squamous cell cancer of the anus . Cancer Detect Prev 2008; 32 : 116–120. [PMC free article] [PubMed] [Google Scholar]
271. Gurney J, Shaw C, Stanley J, et al. Cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis . BMC Cancer 2015; 15 : 897. [PMC free article] [PubMed] [Google Scholar]
272. Bouquie R, Deslandes G, Mazare H, et al. Cannabis and anticancer drugs: societal usage and expected pharmacological interactions – a review . Fundam Clin Pharmacol 2018; 32 : 462–484. [PubMed] [Google Scholar]
273. Taha T, Meiri D, Talhamy S, et al. New drug development and clinical pharmacology cannabis impacts tumor response rate to nivolumab in patients with advanced malignancies . Oncologist 2019; 24 : 549–554. [PMC free article] [PubMed] [Google Scholar]
274. Moreno E, Cavic M, Krivokuca A, et al. The endocannabinoid system as a target in cancer diseases: are we there yet? Front Pharmacol 2019; 10 : 339. [PMC free article] [PubMed] [Google Scholar]
275. Hinz B, Ramer R. Anti-tumour actions of cannabinoids . Br J Pharmacol 2019; 176 : 1384–1394. [PMC free article] [PubMed] [Google Scholar]
276. Thomas BF, Pollard GT. Preparation and distribution of cannabis and cannabis-derived dosage formulations for investigational and therapeutic use in the United States . Front Pharmacol 2016; 7 : 285. [PMC free article] [PubMed] [Google Scholar]
277. ElSohly MA, Mehmedic Z, Foster S, et al. Changes in cannabis potency over the last 2 decades (1995–2014): analysis of current data in the United States . Biol Psychiatry 2016; 79 : 613–619. [PMC free article] [PubMed] [Google Scholar]
278. Chandra S, Radwan MM, Majumdar CG, et al. New trends in cannabis potency in USA and Europe during the last decade (2008–2017) . Eur Arch Psychiatry Clin Neurosci 2019; 269 : 5–15. [PubMed] [Google Scholar]
279. Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity . Eur J Pharmacol 1998; 353 : 23–31. [PubMed] [Google Scholar]
280. Carter GT, Weydt P, Kyashna-Tocha M, et al. Medicinal cannabis: rational guidelines for dosing . IDrugs 2004; 7 : 464–470. [PubMed] [Google Scholar]
281. Brown EG, GnanaDev D, Kirchmeyer K. Guidelines for the recommendation of cannabis for medical purposes . Sacramento: Medical Board of California, 2018. [Google Scholar]
282. Luckett T, Phillips J, Lintzeris N, et al. Clinical trials of medicinal cannabis for appetite-related symptoms from advanced cancer: a survey of preferences, attitudes and beliefs among patients willing to consider participation . Intern Med J 2016; 46 : 1269–1275. [PubMed] [Google Scholar]
283. ASCO’s National cancer opinion survey. Harris Poll on behalf of ASCO . Alexandria, VA: American Society of Clinical Oncology, 2018. [Google Scholar]
Articles from Therapeutic Advances in Medical Oncology are provided here courtesy of SAGE Publications
Daily use of cannabidiol (‘CBD’) oil may be linked to lung cancer regression
It may be worth exploring further the use of cannabidiol (‘CBD’) oil as a potential lung cancer treatment, suggest doctors in BMJ Case Reports after dealing with a daily user whose lung tumour shrank without the aid of conventional treatment.
The body’s own endocannabinoids are involved in various processes, including nerve function, emotion, energy metabolism, pain and inflammation, sleep and immune function.
Chemically similar to these endocannabinoids, cannabinoids can interact with signalling pathways in cells, including cancer cells. They have been studied for use as a primary cancer treatment, but the results have been inconsistent.
Lung cancer remains the second most common cancer in the UK. Despite treatment advances, survival rates remain low at around 15% five years after diagnosis. And average survival without treatment is around 7 months.
The report authors describe the case of a woman in her 80s, diagnosed with non-small cell lung cancer. She also had mild chronic obstructive pulmonary disease (COPD), osteoarthritis, and high blood pressure, for which she was taking various drugs.
She was a smoker, getting through around a pack plus of cigarettes every week (68 packs/year).
Her tumour was 41 mm in size at diagnosis, with no evidence of local or further spread, so was suitable for conventional treatment of surgery, chemotherapy, and radiotherapy. But the woman refused treatment, so was placed under ‘watch and wait’ monitoring, which included regular CT scans every 3-6 months.
These showed that the tumour was progressively shrinking, reducing in size from 41 mm in June 2018 to 10 mm by February 2021, equal to an overall 76% reduction in maximum diameter, averaging 2.4% a month, say the report authors.
When contacted in 2019 to discuss her progress, the woman revealed that she had been taking CBD oil as an alternative self-treatment for her lung cancer since August 2018, shortly after her original diagnosis.
She had done so on the advice of a relative, after witnessing her husband struggle with the side effects of radiotherapy. She said she consistently took 0.5 ml of the oil, usually three times a day, but sometimes twice.
The supplier had advised that the main active ingredients were Δ9-tetrahydrocannabinol (THC) at 19.5%, cannabidiol at around 20%, and tetrahydrocannabinolic acid (THCA) at around 24%.
The supplier also advised that hot food or drinks should be avoided when taking the oil as she might otherwise feel stoned. The woman said she had reduced appetite since taking the oil but had no other obvious ‘side effects’. There were no other changes to her prescribed meds, diet, or lifestyle. And she continued to smoke throughout.
This is just one case report, with only one other similar case reported, caution the authors. And it’s not clear which of the CBD oil ingredients might have been helpful.
“We are unable to confirm the full ingredients of the CBD oil that the patient was taking or to provide information on which of the ingredient(s) may be contributing to the observed tumour regression,” they point out.
And they emphasise: “Although there appears to be a relationship between the intake of CBD oil and the observed tumour regression, we are unable to conclusively confirm that the tumour regression is due to the patient taking CBD oil.”
Cannabis has a long ‘medicinal’ history in modern medicine, having been first introduced in 1842 for its analgesic, sedative, anti-inflammatory, antispasmodic and anticonvulsant effects. And it is widely believed that cannabinoids can help people with chronic pain, anxiety and sleep disorders; cannabinoids are also used in palliative care, the authors add.
“More research is needed to identify the actual mechanism of action, administration pathways, safe dosages, its effects on different types of cancer and any potential adverse side effects when using cannabinoids,” they conclude.
Notes for editors
Please note: out of respect for patient confidentiality we don’t have the names or contact details of the cases reported in this journal.
Funding: None declared
Link to Academy of Medical Sciences labelling system
Externally peer reviewed? Yes
Evidence type: Single case report