What Is Palliative Care?
The Center to Advance Palliative Care (CAPC) defines palliative care as “specialized care for people living with a serious illness” [1]. Palliative care aims to relieve symptoms and stress in multiple domains – physical, psychological, social, and spiritual – with the goal to improve overall quality of life (QOL). Typical symptoms in patients living with serious illness include pain, fatigue, nausea, vomiting, dyspnea, anorexia, and cachexia, among others. A multidisciplinary palliative care team may consist of physicians (who practice Palliative Medicine, an American Board of Medical Specialties), nurses, social workers, aides, therapists, pharmacists, chaplains, and volunteers and serves as an extra layer of support for patients and their families. Palliative care can be provided alongside curative or non-curative treatment and at any stage of disease. While it was traditionally provided in the inpatient setting, palliative care is moving upstream to include the ambulatory, facility, and home settings as well. Palliative care providers help patients and their families navigate complex medical decisions by learning about their patients and focusing on aligning treatment options with patients’ life philosophies and value systems.
The recent resurgence of interest in medical cannabis and support for its use started predominantly with palliative care applications. Compassionate use programs across most states are reflective of this, and of programs that have qualifying criteria, serious illness, and refractory symptoms are common indications for medical marijuana use. As such, palliative medicine specialists may play an important role for those patients who seek medical cannabis treatments.
Role for Cannabis in Symptom Management
Pain
Palliative medicine specialists are experts in managing pain in the setting of active cancers and nonmalignant pain in the setting of a life-limiting serious illness. Chronic nonmalignant pain does not fall within the scope of palliative medicine and is preferably managed by pain medicine specialists.
The role of cannabinoids in pain management is based on the current understanding of the endocannabinoid system (ECS) and its putative role in pain modulation. Cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors are well-studied components of the ECS. CB1 receptors are found on peripheral nerve terminals, and elevated levels are found in areas of the brain that regulate nociceptive processing [2, 3]. CB1 agonists alone produce analgesic effects in the central nervous system (CNS), while both CB1 and CB2 agonists exert analgesic effects peripherally. CB2 is largely located on anti-inflammatory tissues; through modulation of CB2, cannabinoids may exert their anti-inflammatory effects by acting on mast cell receptors to attenuate the release of histamine and serotonin and also antinociceptive effects by stimulating keratinocytes to release endogenous opioids [4, 5]. Endocannabinoids, anandamide (AEA), and 2-arachidonoylglycerol (2-AG) modulate nociceptive signaling through local activation of CB1 receptors. Exogenous phytocannabinoids may regulate neurotransmission and pain signaling within the CNS and immune system.
Cancer Pain
Cancer pain may result from nerve injury, mechanical invasion of pain-sensitive structures, and inflammation. As early as 1975, Noyes et al. explored the effects of synthetic oral delta-9-tetrahydrocannabinol (THC) capsules on cancer pain. The first of two double-blind, placebo-controlled trials measured the pain intensity and pain relief of 10 advanced cancer patients who took 5 mg, 10 mg, 15 mg, and 20 mg of THC or placebo over a 6-hour observation period. It was found that 15 mg and 20 mg doses produced analgesia, though with significant fatigue [6]. Their follow-up study on 34 patients showed that 10 mg of THC produced analgesic effects comparable to 60 mg of codeine [7]. These early studies were limited by small sample sizes, but they led to continued research on cannabinoids for pain management as characterized further. Additionally, these results may inform clinicians about the limited efficacy of cannabinoids in the setting of cancer pain syndromes that often require significant morphine equivalent daily dosing regimens.
Although these early studies used synthetic THC, a more recent study of phytocannabinoids was performed in 2010. This 2-week, multicenter, double-blind trial in Europe investigated the effects of whole-plant extract preparations, nabiximols, in a 1:1 ratio of THC:CBD (cannabidiol) in patients with intractable cancer pain despite optimized opioid therapy. The study showed that the 1:1 extract was superior to THC extract alone or placebo in reducing pain by at least 30% [8]. The follow-up phase III trials of nabiximols for cancer pain demonstrated no improvement in the primary outcome of numerical rating scale (NRS) for pain. However, the experimental group did show improvement in several QOL questionnaires and improvement in sleep with fewer disruptions. This effect was particularly observed in patients from the United States under the age of 65 who were on lower doses of opioids [9]. While evidence for efficacy in cancer-related pain is limited, there may be a possible role of cannabis therapy to address QOL issues.
Further review of the literature reveals distinctions between the patterns of cannabis use between cancer and noncancer patients. In a large cross-sectional study, cancer patients were more likely to use sublingual preparation of cannabis as compared to noncancer patients who were more likely to use an inhaled form [10]. Potential advantages of sublingual preparation of cannabis over inhaled forms include longer duration of action, avoidance of potentially negative pulmonary side effects, and ease of use [10, 11]. This large-scale study showed that medical cannabis users that did not have cancer were more likely to favor inhalation forms through vaporizers, which may raise concerns for potential vaping-related lung injury [10, 12, 13].
Chronic Pain
The data on cannabis use for the treatment of chronic pain conditions is inconclusive. A systematic review of cannabinoids (nabiximols, nabilone, and a fatty acid amide hydrolase inhibitor) found that no studies had a beneficial effect for pain in patients with rheumatoid arthritis, fibromyalgia, or osteoarthritis. Treatment groups also experienced frequent side effects and withdrawals due to those side effects [14]. A randomized, double-blind, placebo-controlled, parallel-design clinical study on the use of oral THC in a dose-escalation fashion in patients with chronic abdominal pain secondary to chronic pancreatitis or surgery showed that, despite adequate absorption of THC, pain intensity did not reduce [15]. A 2017 systematic review on the effects of cannabis among adults for chronic pain concluded that there was insufficient evidence to support its use for non-neuropathic chronic pain conditions, as well as limited evidence showing increased risk for adverse mental health effects [16]. Based on this data, cannabis does not appear to be effective for chronic, nonmalignant, nociceptive pain conditions.
Neuropathic Pain
The most compelling data to support cannabis use for pain management is for neuropathic pain, with several high-quality studies demonstrating its efficacy. A 2015 systematic review and meta-analysis of mostly cannabinoids for neuropathic pain showed greater reduction in pain as compared to the placebo condition [17]. It must be noted, however, that more than half of these studies used synthetic compounds or nabiximols, which may be vastly different from dispensary cannabis products that are available with differing potency and variable oversight. Furthermore, the pain reduction seen in cancer pain syndromes was later debunked with phase III trials of nabiximols.
In 2016, a placebo-controlled, crossover, randomized control trial (RCT) using vaporized cannabis in patients with central neuropathic pain from spinal cord injury showed reduction in neuropathic pain scale ratings without a dose-dependent effect [18]. A similar phase I study on vaporized cannabis for central pain demonstrated similar analgesic effects for both low (2.9%) and high (6.7%) THC concentrations of cannabis with dose-dependent psychoactive side effects (feelings of drunkenness, confusion, difficulty paying attention). Based on this, the investigators concluded that lower potency of THC strains may be preferable due to the similar efficacy with fewer adverse side effects [19]. Another study comparing low (3.5%) versus high (7%) THC levels in smoked cannabis on central and peripheral neuropathic pain demonstrated similar antinociceptive effects, but both groups had increased feelings of impairment, desire for more drug, sedation, and confusion when compared to placebo. Feelings of being “high” and “stoned” and neurocognitive impairments in attention, learning, memory, and psychomotor speed were significantly greater in the higher concentration group as compared to the lower concentration group that exhibited only a decline in learning and memory [20]. These studies suggest a narrow therapeutic window for THC between 2.9% and 3.5% to achieve neuropathic pain relief and minimize potential psychoactive and neurocognitive side effects. The national average of THC potency, however, ranges from 14% to 17% and rising from 4% in 1995 to 12% in 2014 and 17.1% in 2017 [21, 22]. Marijuana concentrates are even more potent, the 2017 Colorado Marijuana Market Size and Demand Study reveals, and THC potency in concentrates jumped from 56.6% in 2014 to 68.6% in 2017 [23]. Shatter and wax, which are forms of concentrates, boast a THC potency as high as 80% [23]. These figures are way above the therapeutic window for pain relief.
In addition to these studies that focus on central pain, there are others that examine peripheral neuropathic conditions. A recent meta-analysis of inhaled cannabis in chronic painful neuropathy showed that inhaled cannabis reduces pain by at least 30% with a number needed to treat (NNT) of one out every five to six patients [24]. While this is promising evidence, the analysis was limited by the small number of studies, potential detection, and performance biases, and the investigators were unable to draw firm conclusions regarding sustained long-term benefits and risk in the community setting [24]. A small, randomized, double-blinded, placebo-controlled, crossover clinical study of patients with diabetic neuropathy showed that vaporized cannabis reduced pain in a dose-dependent manner, with the most consistent effect observed in patients receiving 28 mg THC (CBD content <1%). Medium- and low-dose (16 mg and 4 mg, respectively) THC also resulted in significant reduction in pain intensity scores. Pain reduction was observed as early as 15 minutes and effects were sustained for at least 4 hours [25]. A prospective, placebo-controlled RCT demonstrated efficacy of smoked cannabis cigarettes (THC concentration of 3.56%) in reducing chronic neuropathic pain in HIV-associated peripheral neuropathy [26]. These results were replicated in later studies; however, these studies were small, had short durations, and were not placebo-controlled.
At the time of this writing, the American Academy of Neurology (AAN) position statement on medical marijuana “recognizes that medical marijuana may be useful in treating neurological disorders” and associated symptoms such as pain but also calls for rigorous research to evaluate long-term safety and efficacy of medical marijuana and its compounds. Its favorable position is based on a systematic review of cannabis extract showing efficacy in pain and spasticity management in multiple sclerosis [27, 28]. However, because the safety and efficacy profiles are still uncertain, the AAN further states that it “does not support or advocate for the legalization of medical marijuana for use in neurological disorders at this time.” Further research is needed to determine the long-term safety and potential benefits [29].
Nausea
Nausea, the unpleasant sensation of needing to vomit, can occur with or without accompanying vomiting. It is present in up to 80% of cancer patients and even higher in the last days of life [30]. Nausea in the palliative care setting, can result from many causes: drug-induced, conditioned responses (i.e., anticipatory nausea), gastrointestinal origin (e.g., hepatic stretch, gastroparesis, peritoneal inflammation), or central origin (e.g., vestibular dysfunction and brain metastases), among others. The ECS is widely distributed along the gut-brain axis and is purported to play a role in regulating the nausea-vomiting pathway [31].
Chemotherapy-induced nausea and vomiting (CINV) in particular can develop in up to 80% of those receiving chemotherapy and has been well studied [32]. CINV is divided into anticipatory, acute (within 24 hours of medication administration), delayed (greater than 24 hours after medication administration), breakthrough, and refractory. Chemotherapy is thought to induce nausea and vomiting by way of many neurophysiological pathways such as direct stimulation of the chemoreceptor trigger zone, activation of the area postrema, activation of cortical pathways, and activation of peripheral pathways.
There are studies from as early as the 1970s showing the benefits of cannabis-based medications, with the synthetic cannabinoid THC being most commonly studied. Chang et al. performed a placebo-controlled, clinical RCT with 15 patients that showed an incidence of nausea and vomiting of 6–44% depending on the plasma concentration of THC, as compared to 72% for the control group [33]. Since the availability of nabilone, a synthetic THC analogue, and dronabinol, synthetic THC, for treatment of CINV in 1985 and 2006, respectively, several studies and reviews have confirmed the efficacy of cannabinoids for CINV.
A systematic review by Tramer et al. analyzed 30 clinical trials which studied oral dronabinol, oral nabilone, and intramuscular levonantradol [34]. Cannabinoids were found to be more effective than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride for complete control of nausea, though not for very low or very high emetogenic chemotherapy. A later review by Amar in 2006 evaluated 15 studies with nabilone and 14 with dronabinol. Nabilone was superior to prochlorperazine, domperidone, and alizapride for treating CINV, leading to its FDA approval [35].
A more recent Cochrane Review in 2015 looked at 23 RCTs performed between 1975 and 1991 with moderate to highly emetogenic chemotherapy regimens. It found that, compared with placebo, patients were more likely to report absence of nausea and vomiting when cannabinoids were administered, though also more likely to withdraw from the experiments for adverse effects. Furthermore, patients reported a preference of cannabinoids over placebo. There was no evidence of difference between cannabinoids and prochlorperazine or other antiemetics. To note, however, the quality of evidence was rated as low. Another review showed that cannabinoids were more effective than the more typical antiemetics prochlorperazine, metoclopramide, chlorpromazine, and haloperidol [36]. Despite the efficacy of these medications, it should be noted that side effects can also limit widespread use.
While there are sufficient data for the efficacy of synthetic cannabinoids, the evidence for phytocannabinoids is more limited. A 2015 review by Kramer et al. reviewed two studies that looked at smoked marijuana: one study of 15 patients showed benefit in reducing nausea and vomiting, while the other study of 8 patients did not [37]. Medical cannabis may play a role in palliation of nausea and vomiting despite optimized trials of standard antiemetics including synthetic cannabinoids. Further studies are needed to demonstrate comparative efficacy and safety to standard antiemetics.
Anorexia and Cachexia (Dysgeusia)
The ECS may play a role in modulating appetite via CB1 receptors [38, 39] by reinforcing the motivation to find and consume food with high-incentive value and regulating levels and actions of orexigenic and anorectic mediators [40, 41]. Cannabinoids or, more specifically, pharmaceutical THC drugs have been shown to stimulate appetite in patients with AIDS [42]. However, studies of patients with cancer-related anorexia-cachexia syndrome (CACS) do not demonstrate efficacy [43]. One phase III trial did show that patients with CACS had increased appetite with cannabis extract and THC; however, there was no significant difference compared to placebo in appetite, QOL, mood, or nausea [43]. In patients with CACS, megestrol was found to be superior to dronabinol (2.5 mg twice daily) alone or as adjunctive treatment of megestrol for palliation of anorexia [44].
Dysgeusia is a major complaint of patients on chemotherapy that contributes to anorexia and negatively impacts QOL. In 2011, a double-blind, placebo-controlled, pilot RCT showed that administration of dronabinol to advanced cancer patients with poor appetite and chemosensory alterations resulted in improved and enhanced chemosensory perception and food taste, but no significant differences were seen in appetite, caloric consumption, or QOL scores between the control and treatment groups [45].
Shortness of Breath
Dyspnea is a very commonly reported symptom in palliative care patients. A study done by Pickering et al. found no statistical difference in visual analogue scale (VAS) dyspnea scores in a small RCT in 2011 [45]. While there is no evidence to link smoking marijuana and lung cancer as there is with cigarette smoking, several studies have shown an association between smoking marijuana and the development of chronic bronchitis symptoms [46]. At the time of this writing, there is also a growing concern for the association between vaping devices and lung illness; there have been 380 reported cases and 6 deaths and all cases have a history of using vape devices [47]. Current evidence does not support the use of cannabinoids for dyspnea.
Fatigue
There is evidence that suggests that cannabis may also help alleviate symptoms associated with fatigue. Frequent users report that marijuana gives them mental clarity and focus, but larger-scale controlled studies are lacking. A small 2017 study looking at performance and mood disruptions during simulated night shift work showed that smoking THC reduced disruptions in inhibitory control, recall, sustained attention, and reaction time in a dose- and time-dependent manner and that its participants reported feeling markedly more stimulated and less tired [48]. A caveat to this study is that it was very small with only 10 subjects, and the simulated conditions of shift work may not be reflective of the fatigue that often accompanies serious illness. Another survey study of 538 people with Parkinson’s disease and multiple sclerosis found that, compared to non-cannabis users, cannabis users reported less fatigue [49].
However, there is conflicting data that excessive daytime sleepiness is also associated with cannabis use [50]. This seemingly contradictory effect may be explained by recent work demonstrating CBD as a wake-promoting agent and its ability to counteract the sedative effect of THC [51, 52]. The various effects of cannabis on fatigue may be attributed to the different composition of cannabinoids between cannabis products. Further research is needed to better understand the optimal cannabinoid profiles to help with fatigue management.
Insomnia
Studies of medicinal cannabis users have identified insomnia as a common indication for its use. Cannabinoid concentration, dose, and route of administration may have different effects on sleep quality and insomnia symptoms as evidenced by the conflicting and mixed results found in the literature. According to some studies, the role of CBD in the sleep-wake cycle is dose-dependent, with higher doses resulting in increased sleep duration and decreased arousal [53], while lower doses of CBD increases wakefulness, producing a stimulating effect [52, 54]. For THC, a dose of 15 mg resulted in increased sleepiness and delayed sleep onset on the following day after administration [52], and chronic administration of THC was associated with tolerance to its soporific effects [55]. A cross-sectional study of medical cannabis users with insomnia and sleep latency was more likely to use higher CBD concentrations, and there was an association between higher THC doses and decreased hypnotic medication use [56]. Another study found that medicinal cannabis users, both with and without reported sleep problems, experienced decreased sleep latency after cannabis use [57].
Studies of individual cannabinoids (THC and CBD) on sleep quality and insomnia show conflicting results. Both phytocannabinoids and synthetic THC were associated with decreased sleep latency [52, 58], but one study with synthetic THC administration found that the overall amount of nighttime sleep decreased over time, suggestive of a tolerance effect [58]. One of these studies found that, when combined with CBD, THC decreased stage 3 non-rapid eye movement (NREM) sleep, which is the most restorative stage of sleep [54]. Another study on CBD found that it blocked anxiety-induced rapid eye movement (REM) sleep suppression with no effect on NREM sleep [59]. Similarly, anecdotal evidence showed that administration of CBD oil reduced insomnia symptoms and sleep disturbances related to post-traumatic stress disorder (PTSD) [60], suggesting that CBD may impact sleep quality through its anxiolytic effects.
Conclusive data on cannabis for sleep is lacking and further evidence is needed to determine efficacy and duration of treatment for different sleep disorders before this can be a recommended treatment for insomnia.
Anxiety
As with the management of other symptoms, the effects of cannabis on mood are dependent on the composition of its various cannabinoids. Previous studies garnered evidence supporting the anxiolytic and antipsychotic effects of CBD that seem to counteract THC-induced anxiety [61, 62] with lower doses of THC producing anxiolytic effects and higher doses produce anxiogenic effects [63].
THC doses between 1.25 and 30 mg were shown to decrease anxiety in a biphasic, dose-dependent manner in healthy adults [64]. Studies of dronabinol showed that administration of 7.5 mg resulted in reduced limbic reactivity in the lateral amygdala, which is the brain’s emotion processing center, to angry or fearful faces [65]. CBD has been shown to produce anxiolytic effects and counteracts the anxiogenic effects of THC, with doses of 300–400 mg producing the same effects as ipsapirone, a serotonin 1A (5HT1A) receptor partial agonist in healthy participants [66, 67]. While it may be known that cannabis may induce feelings of dysphoria, anxiety, and panic, studies demonstrate that cannabis generally reduces anxiety when administered at lower doses with CBD activating CB1 receptors on glutamatergic cortical neurons, offsetting anxiogenic effects of THC regulated by CB1 receptors on GABAergic forebrain activity [68].
A 2019 systematic review evaluating cannabidiol use in psychiatric disorders identified two completed RCTs exploring the efficacy of acute administration of CBD on anxiety symptoms in patients with social anxiety disorder (SAD). The first, a double-blind RCT with 24 never-treated SAD patients who received 600 mg CBD versus placebo and compared to healthy controls after a simulated public speaking test (SPST) showed significant inhibition in fear of public speaking in the CBD group when compared to placebo [69]. A second within-subject, crossover design RCT with 10 participants compared 400 mg of CBD versus placebo with CBD being associated with significantly decreased levels of anxiety compared to placebo [70]. Currently, a double-blind, placebo-controlled RCT of 50 adults with primary SAD, generalized anxiety disorder (GAD), and panic disorder (PD) is comparing the efficacy and safety of flexibly dosed CBD oil capsules versus placebo [71]. As mentioned earlier, a double-blind placebo RCT of 40 healthy individuals showed that compared to ipsapirone (5 mg) and diazepam (10 mg), 300 mg CBD successfully decreased anxiety after SPST [66]. More recently, in another double-blind study in healthy volunteers, 300 mg of CBD in powder form was identified as the optimal therapeutic dose when compared to placebo to treat SPST-induced anxiety [72]. Taken together, it is likely that any anxiolytic effects of cannabis are primarily CBD-mediated.
Depression
One of the most common known effects of cannabis is a sense of euphoria. Although there is much interest in using these possible euphoric effects to treat depression, there are only case reports [65, 73–75], and large clinical studies do not support cannabis-based medicines for this indication. Furthermore, use of rimonabant, a CB1 receptor antagonist, increased indices of depression and suicidal ideation in healthy individuals, and rimonabant was subsequently taken off the market due to its severe side effects [64].
The ECS is involved in the clinical effect of various antidepressants. Studies have shown that chronic treatment with tricyclic antidepressants (TCAs) is associated with increased CB1 receptor density in the hippocampus and hypothalamus and reduced hypothalamic-pituitary-adrenal (HPA) axis activation by stressing stimuli [75, 76]. 2-AG is one of the main endocannabinoids and has its own mimetic phytocannabinoid, CBD; AEA is another endocannabinoid with THC as its mimetic phytocannabinoid. Reduced circulating levels of both endocannabinoids 2-AG and AEA were found in patients with major depressive disorder (MDD) [77, 78]. There are studies that also implicate that genetic variability in ECS regulation can influence susceptibility to mood disorders [79]. Genetic polymorphisms of the ECS have been associated with depressive symptoms and may influence response to antidepressant treatment [80–83]. Despite this preclinical data, there is no high-quality evidence to support the use of phytocannabinoids for depression.
Delirium and Agitation
Prevalence of delirium in the inpatient palliative care setting is reported to be as high as 42% and can be burdensome for patients as well as their caregivers [84]. Treatment of delirium includes both nonpharmacologic and pharmacologic approaches to address modifiable risk factors. There have been a few studies that show that dronabinol can be a good adjunct to standard regimens to decrease the neuropsychiatric symptoms of dementia, including decrease in negative affect, agitation, motor behavior, nighttime disturbances, irritability, and sundowning [85, 86]. A retrospective cohort study published in 2014 showed an association between addition of dronabinol to standard treatment regimens and decreased aberrant vocalizations, motor agitation, aggressiveness, and resistance to care in geriatric patients with dementia [87].
An important note to consider is that synthetic cannabinoids, particularly THC, can worsen psychosis in those with underlying disease or cause new-onset delirium or psychosis in those without underlying mental health disorders [88]. Interestingly, cannabinoid use may be helpful in the treatment of delirium secondary to cannabis intoxication. Levin et al. showed decreased withdrawal symptoms when 10–20 mg of dronabinol was administered daily [89]. Allsop et al. in 2014 found similar results with administration of THC (maximum daily dose of 86.4 mg) and 80 mg of CBD [90]. While there is some literature to support use for cannabis intoxication, evidence to support its use in other settings is more limited. Concern for potential neurotoxic excitation and agitated delirium caused by excessive doses of cannabinoids need to be considered in palliative care patients with potentially limited CNS reserve, especially with unregulated doses of THC that are becoming more widely available [91].
Quality of Life and Existential Distress
Patients living with serious illnesses and accompanying functional loss often experience spiritual and/or existential distress which can be manifested as meaninglessness, hopelessness, being a burden on others, or questioning life itself. Survey-based studies that elicit motivations for cannabis use in the cancer population, such as that done by Pergam et al., reveal that people admit to using cannabis for stress reduction, improvement of QOL, and dealing with this type of distress [92]. Current approaches to relieving existential distress include cognitive behavioral interventions, hypnotically facilitated therapy, meaning-centered psychotherapy, and dignity therapy. These interventions often aim to discuss concerns regarding death and dying openly and clarify new life goals to help create new meaning for patients [93, 94]. Anecdotally and based on clinical experience, there is a subset of patients that appreciates that the euphoric effects of cannabis can create similar results. SK Aggarwal also suggests that “a mild euphoria,” “reduction of psychological trauma,” and the “increased introspection and meditation” that can result from cannabis use may be helpful in alleviating existential distress [95]. This is an important domain of palliative care for which medical cannabis may provide benefit and more research is needed.
Precautions for Cannabis Use in Palliative Care
Possible side effects of cannabis by organ system
Psychiatric | Alteration of perception, time distortion, paranoia, anxiety, hallucinations [99] |
Neurological | Somnolence, fatigue, memory impairment, dizziness. Cardiovascular events including cerebral vasoconstriction can lead to cerebral ischemia and sleep disturbance [61–63, 155, 156] |
Eyes, ears, nose, throat | Reddened eyes, reduced tear flow, photophobia, xerostomia, dental caries [124, 129, 157, 158] |
Cardiovascular | Hyperadrenergic state, hypertension, tachycardia, orthostasis, arrhythmia, selective vasodilation/vasoconstriction [100–103] |
Pulmonary | Bronchodilation – all forms Cough, wheezes, shortness of breath, increased sputum – when smoked [129, 139, 157, 159] |
Gastrointestinal | Nausea, vomiting, increased appetite [145] |
Genitourinary | Sperm impairment, possibly erectile dysfunction [8, 118, 148, 160] |
Immunologic |
Naturally occurring cannabis plant species produce a group of molecules called phytocannabinoids (plant-based cannabinoids), of which there are over 100 types, and they have varying degrees of effects on the human body [97]. Two of the most active and abundant phytocannabinoids are THC and CBD [96, 98]. THC is known to exert most of the known psychoactive and physiological effects by acting on two endogenous receptors, CB1 and CB2. Unlike THC, CBD lacks detectable psychoactive properties and is believed to have lower affinity for CB1 and CB2. CBD is thought to counteract some of the effects of THC [99]. While the actions exerted on CB1 and CB2 by THC and CBD account for their therapeutic effects, they are also the cause of many side effects that we will discuss in this section.
Side Effects
The side effects of cannabis described in the literature generally occur within 30 minutes to 1 hour of consumption and last 2–4 hours after. Eye redness, caused by dilation of blood vessels in the eye, is one of the most notorious side effects associated with cannabis use [100]. THC also has other effects on the eyes, such as reducing intraocular pressure, decreasing tear flow, and causing photophobia. The mechanism by which photophobia occurs is not entirely clear, but it may be due to palpebral fissure narrowing and eyelid ptosis.
Dry mouth (xerostomia) is another very common side effect experienced by cannabis users. This is thought to be caused by the parasympatholytic properties seen in cannabis [101]. Xerostomia has been found to be beneficial in some palliative care patients, namely, head and neck cancer patients who benefit from decreased secretions [102]. This can, however, increase the incidence rate of dental caries and may also be a negative side effect in patients who already suffer from dry mouth [101].
Less commonly known side effects of cannabis include its effects on the reproductive system. Early research supported the idea that marijuana use increased sexual desire, quality of orgasms, and emotional intimacy [103]. Over time, some of the negative effects have come to light as more recent data suggests that chronic cannabis use can reduce sperm count, concentration, and motility, in addition to causing abnormalities in sperm morphology [104]. Animal studies on rats have shown that CB1 activation by THC can cause erectile dysfunction, but there has not yet been sufficient data to show either beneficial or detrimental effects on erectile function in humans [105].
Psychological
In 2006, 12 students from the University of California at Berkeley were taken to a local hospital after eating marijuana cookies, brownies, and cookie dough. They were described as having severe anxiety and “feelings of doom” due to the ingestion [106]. In 2016, two young men became paranoid after ingesting large amounts of marijuana and called 911 on themselves; they were convinced that they were surrounded by undercover police officers [107]. A study from 2015 showed definitively that intravenous THC increases paranoia when compared to the placebo treatment [108]. Interestingly, informing subjects that THC can cause paranoia increased the likelihood of the event. Subjects that had THC-induced anxiety were more likely to have paranoid ideations.
There is a dose-dependent effect of THC on anxiety, with low doses potentially having an anxiolytic effect and higher doses leading to increased rates of anxiety [109]. It is hypothesized that the complex interaction of the ECS with the amygdala, dopaminergic-dependent brain regions, and HPA axis are responsible for inducing and relieving anxiety. Among studies looking at medical cannabis use for pain, anxiety remains a common side effect, while frank paranoia and psychosis are reported to a lesser degree [110].
Special care should be taken to inform patients about these potentially distressing side effects when starting medical cannabinoids. Recommending medical cannabis to patients with schizophrenia, schizoaffective disorder, or other psychotic disorders should be avoided. Despite associations between schizophrenia and recreational marijuana use, a causal link has not been established. However, there is a concerning association between cannabis use and earlier onset of psychosis, adverse course of psychotic symptoms with exacerbation of symptoms, and negative course of illness [111, 112]. Acute cannabinoid use can induce psychotic symptoms including suspicious and persecutory paranoia, grandiose delusions, conceptual disorganization, fragmented thinking, and perceptual alterations, which can be indistinguishable from those seen in schizophrenia [113]. Additionally, individuals who use large amounts of cannabis at younger ages are more likely to develop mental health disorders in the future [114]. While these psychiatric side effects are often short-lived, prolonged symptoms may occur depending on the method of delivery. Given the dose-dependent nature of psychiatric side effects, it is generally recommended that patients start at a low dose and increase as tolerated.
Neurological
The distribution of the CB1 receptors throughout the brain is generally considered to be the culprit of the neurological side effects seen mainly with THC. Early RCTs of nabilone for CINV revealed dizziness as one of the most common side effects of the medication [50, 115]. Over time, trials assessing the therapeutic benefits of synthetic cannabinoids for a variety of uses in palliative care populations support the findings from these early trials [116–118]. The dizziness induced by cannabinoids is thought to be caused by the CB1 receptors located within cells of the cerebellum [119]. Dizziness should always be considered and discussed when recommending cannabinoids, and it is especially important in palliative care patients who often have underlying mobility impairment and increased frailty.
Among palliative care patients, the other extremely important side effect to consider is sleep disturbance. In general, studies have shown that cannabinoids increase sleep quality and can decrease sleep disturbances [120]. Drowsiness is one of the most common side effects described in multiple clinical trials [110]. While this may be helpful in patients that cannot sleep because of severe pain, it may be detrimental to patients with fatigue from end-stage diseases. Furthermore, chronic cannabis users may experience worse sleep when coming off the substance, so patients should be counseled on this aspect if they plan to stop or decrease use of cannabis.
Memory is another area that is highly affected by THC. Among the many aspects of memory, both delayed and immediate word list recall seem to be affected the most [121]. In adults, working memory worsens with marijuana use, with higher use correlating with worse working memory (multiple tasks on the Wechsler Adult Intelligence Scale) [122]. These issues seem to resolve with periods of abstinence. Other domains of executive functioning also seem to be affected by both acute and chronic cannabis use. Planning, attention, reasoning, and problem-solving each seem to be affected to varying degrees. These effects seem to be more pronounced in older adults and, only rarely, within particular domains, may persist after discontinuation of use [122, 123]. Further studies are needed to better understand the impact of these side effects, particularly in geriatric populations of cannabis users who may be more susceptible due to underlying baseline cognitive and mobility dysfunction.
Cerebrovascular
Another major neurological side effect to consider is strokes, with which marijuana use has been loosely associated. There have been case reports and case series of patients presenting with strokes after ingestion of marijuana [124–127]. In an epidemiologic study looking at young patients presenting with cerebral infarction, 6% of 422 patients reported cannabis as the only drug that was taken prior to the event [128]. Furthermore, animal studies have shown that THC exerts a concentration-dependent vasoconstriction effect on blood vessels in the brain [129]. This could be a potential mechanism for marijuana to cause ischemic stroke. Relative hypotension from systemic vasodilation or sympathetic surge after ingestion could also be contributing factors. The data supporting an association between cannabis use and cerebrovascular events at this time remains scant, and more studies are required to clearly delineate a causative effect.
Cardiovascular
One of the first physiologic studies pertaining to cannabis use was from 1969, where it was noted that there was a moderate increase in heart rate after using marijuana [130]. Since that time, it has become clear that this increase in heart rate is likely due to THC’s effects on the autonomic nervous system, namely, simultaneous stimulation of the sympathetic system and inhibition of the parasympathetic system [131]. The effects cause an increase in cardiac output with catecholamine release that can last up to 2 hours [132]. Cannabis generally causes a slight increase in systolic blood pressure and a slight decrease in diastolic blood pressure because it also has vasodilatory effects on the peripheral vasculature [133]. This drop in diastolic pressure can lead to orthostatic hypotension, dizziness, and syncope [134]. It should be noted that these physiologic changes seem to diminish with chronic cannabis use [134, 135].
The increase in sympathetic tone during THC ingestion inevitably increases the heart’s oxygen requirements and can therefore worsen underlying angina [136, 137]. Many studies looking at cardiac ischemia from marijuana use had subjects smoke marijuana which can increase carboxyhemoglobin and worsen blood oxygen levels. There have also been numerous case reports and case series on marijuana-inducing cardiac arrhythmias from atrial fibrillation to ventricular tachycardia, and this is thought to be from increased sinoatrial and atrioventricular nodal conduction in addition to enhanced sinus automaticity [138–142]. It is unknown whether or not these cardiovascular effects can occur in non-smoking forms of cannabis.
Given that patients seen in palliative care usually have multiple chronic comorbidities, it is very important to assess a patient’s underlying cardiac function. Patients should be counseled on the possible cardiac side effects and make sure to contact providers if they experience any symptoms that could indicate an arrhythmia or cardiac ischemia. It may be reasonable to forgo treatment with medical cannabis if a patient has underlying arrhythmias, heart failure, or hypotension, depending on their goals of care. For example, if one’s goal is solely QOL for which cannabis may be beneficial, they may opt to use cannabis despite its potential impact on shortening quantity of life.
Pulmonary
While cannabis can be ingested in multiple ways, smoking has historically been the most common mode of ingestion. Countless publications from throughout the 1900s looked at how smoking cannabis affects the lungs. Studies have shown that smoking marijuana chronically correlates with higher rates of asthma, bronchitis, cough, shortness of breath, and wheezing [143]. While smoking marijuana does have implications on the respiratory tract, this does not necessarily apply to FDA-approved cannabinoid formulations.
There have not been any studies looking specifically at orally ingested cannabinoids and effects on the pulmonary system. We can extrapolate from past studies on aerosolized THC inhalation to infer that orally ingested cannabis likely causes a similar effect on bronchodilation, with increases in forced expiratory volume (FEV1) [144, 145]. In multiple clinical trials looking at orally ingested cannabis medications, there does not seem to be any common pulmonary side effects [8, 17, 117, 118, 146].
Electronic cigarettes (e-cigarettes) are a new form of inhaling nicotine and marijuana oils and are commonly referred to as “vaping.” The electronic devices aerosolize oils containing THC or nicotine, flavoring, and other chemicals that are then inhaled [147]. As of September 2019, an ongoing multistate investigation by the Center of Disease Control (CDC) on cases of severe pulmonary disease related to “vaping” was underway with the first cases sprouting in Wisconsin and Illinois [12]. More than 25 states have reported at least 215 possible cases, and rising, of severe pulmonary disease associated with vaping THC, nicotine, or both; at least two reported deaths have also been reported to the CDC [13]. As such, while the safety, or lack thereof, of vaping is being investigated, users should consider discontinuing this form of THC administration. At the very least, if vaping is continued, users should monitor themselves for symptoms and seek prompt medical attention if needed.
Gastrointestinal
Cannabinoids may help with appetite and alleviate nausea and vomiting. While there seems to be an improvement in nausea and vomiting in multiple studies, there is also a paradoxical increase in nausea and vomiting in some chronic cannabis users [148]. Long-term cannabis use may cause increased secretion and activation of corticotropin-release leading to this paradoxical increase in nausea and vomiting [149]. These effects are exaggerated in cannabinoid hyperemesis syndrome.
There are many studies of cannabis for different pain indications. In a number of these studies, nausea, dizziness, and vomiting are some of the most common adverse events. For example, in a 2010 placebo-controlled RCT investigating the efficacy of THC:CBD in patients with advanced cancer, there was a significant worsening of nausea and vomiting scores in the treatment group when compared to placebo. A trial from the Journal of Pain looking at the effects of various doses of nabiximols on cancer-related symptoms showed a dose-related incidence of adverse outcomes [118]. Subjects who received higher doses of nabiximols had higher rates of both nausea and vomiting. For subjects who received any dose of nabiximols, 22% had nausea and 16% had vomiting. This was higher than the placebo group where 13% of subjects reported nausea and 8% reported vomiting [118]. In a meta-analysis looking at cannabinoids as compared to placebo, a total of 3,529 subjects (from 30 different studies) reported nausea, giving it a summary odds ratio of 2.08 [17].
Orexigenic effects of cannabis may help cancer patients. Animal models and clinical studies demonstrate a role for the ECS in eating motivation [17, 150]. While these effects are often desired in palliative care patients, for others this may worsen obesity and metabolic syndrome.
Recent data on Epidiolex, a CBD oral solution derived from plant extract that is FDA-approved for seizures in Lennox-Gastaut syndrome and Dravet syndrome, is concerning for effects on the liver [151–153]. Up to 10% of patients showed alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels greater than three times the upper limit of normal. Of these patients, 78% were also on valproic acid while 22% were not [151]. Liver enzyme levels returned to normal after stopping or decreasing the dose of Epidiolex or other anti-seizure medications like valproic acid. There was no significant increase in bilirubin to indicate severe drug-induced liver injury [99]. As new indications for using CBD arise, its effects on the liver, especially for those who may have underlying dysfunction, will be important to monitor.
Immunologic
The ECS plays a role in the immune system. Concern that cannabinoids may affect the immune system derives from studies of nabiximols. In clinical studies of this marijuana-derived CBD extract, patients had up to a 41% chance of infections, greater than that of the placebo group [152]. Potential immune system dysregulation should be considered when offering cannabis-based medicines to frail palliative care patients.
Additionally, there have been reports of contaminated cannabis at dispensaries [43–45]. In 2017, CBS News reported on a California man undergoing intensive chemotherapy treatment with concurrent medical marijuana use to stave off treatment effects. The patient died from a rare lethal fungal infection as a result of medicinal marijuana use. Physician researchers at UC Davis performed a study on 20 marijuana samples and found them to contain multiple contaminants of bacterial and fungal pathogens including Cryptococcus, Mucor, Aspergillus, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii [154]. In an already immunocompromised individual, such as a cancer patient undergoing chemotherapy, exposure to such pathogens may be fatal. These potential risks should be discussed with patients before initiating cannabis-based treatments.
Drug-Drug Interactions
Drug metabolism is an extremely complex system by which active components of medications are broken down by enzymes. Both THC and CBD are metabolized in the liver. THC, for example, is oxidized by the enzyme cytochrome P450 (CYP) 2C9 to the primary psychoactive metabolite 11-hydroxy-THC [161], and then further broken down by CYP3A4. THC is known to inhibit the hepatic CYP2C9 enzyme, and this could potentially lead to an increased level of the medications that this enzyme would otherwise metabolize (including but not limited to NSAIDs, sulfonylureas, warfarin, antidepressants, and antiepileptics) [161]. There have been case reports of patients with high international normalized ratio (INR) values due to CYP inhibition by THC [162]. CBD exerts an inhibitory effect on both CYP2C19 and CYP3A4. Data on CBD’s interaction with typical medications is scant, but there is an emerging body of evidence that Epidiolex can increase levels of valproic acid, phenytoin, and clobazam [161].
At this time, formal pharmacokinetic studies on how cannabinoids interact with commonly prescribed medications are lacking. Additionally, the inconsistent formulation of various products makes predicting drug interactions difficult. With the availability of more concentrated formulations of CBD, caution should be used with patients on medications that are metabolized by CYP2C19 and CYP3A4. Similarly, with the rise of THC concentrations in some preparations of cannabis, patients may need careful monitoring for potential drug interactions.
Best Practices for the Palliative Care Provider
While discussing the role of cannabis in addressing patient symptoms, it is important to keep the prognosis and intent of treatment (e.g., curative or palliative) in mind. Some cancer- or treatment-related side effects may subside after treatments are completed or treatment dosages are reduced. For instance, a patient receiving radiation therapy can have acute pain that should improve by several weeks after radiation. This patient may be an appropriate candidate for medical cannabis but for a time-limited period. Discussions about treatment duration and expectations are important to set appropriate boundaries and indications for cannabis use. Due to the limited data on the safety profile of medical cannabis, goals of care conversations are necessary to weigh the potential benefits based on limited data versus theoretical and known risks before continuation of cannabis-based treatments.
Although patient counseling guidelines regarding medical cannabis have not been standardized, treatment discussions should include type (such as strain, formulation, etc.), expected benefits and adverse effects, onset of action, dose (doses of cannabinoids if known), route of administration, precautions, and interactions [163]. One way to augment counseling efforts regarding medical cannabis would be to extrapolate from the concepts derived from opioid pain management and use a written agreement. Although the liability and legal ramifications of cannabis agreement forms are yet unknown, examples of such can be found and should be considered by cannabis practitioners [164].