Medical Cannabis for Best Supportive Care of Patients Affected by Cancers of the Head and Neck: A Narrative Review

Phytocannabinoids, Synthetic Cannabinoids, and Endocannabinoids

More than 500 compounds have been reported from C. sativa, of which 125 cannabinoids have been isolated and/or identified as cannabinoids. Cannabinoids are C21 terpeno-phenolic compounds specific to Cannabis. The non-cannabinoids are non-cannabinoid phenols, flavonoids, terpenes, alkaloids and others (7), which contribute to the “entourage effect”. The entourage effect refers to the phenomenon whereby cannabis compounds, when consumed together, produce different effects than the individual components alone. This synergy between phytocannabinoids, terpenes, and flavonoids may explain the variability of experiences and therapeutic effects that cannabis produces (8).

There are three main classes of cannabinoids including phytocannabinoids, synthetic cannabinoids, and endocannabinoids. Phytocannabinoids (plant-derived, such as those from cannabis) are compounds unique to the cannabis plant that interact with the human endocannabinoid system. The most well-known are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), but there are over 100 phytocannabinoids with different properties (Figure 1). CBD was first isolated from marijuana in 1940, and its structure was reported in 1963 (9). However, because CBD is non-psychoactive, it was initially overlooked in favor of THC. The structure of THC, the primary psychoactive compound, was identified by Mechoulam and Gaoni in 1964 (10, 11), sparking research into the effects of cannabinoids on the brain and body. CBD has a different interaction profile with cannabinoid receptors than THC. It is known for its anxiolytic, anti-inflammatory, and anticonvulsant effects, which is why it is widely used in treatments for epilepsy and anxiety. Although generally well tolerated, CBD may interact with some medications, such as anticoagulants, increasing the risk of side effects. THC interacts predominantly with the CB1 receptors of the endocannabinoid system, located primarily in the central nervous system (CNS), producing effects such as euphoria, altered sensory perception, and pain relief. Additionally, THC is known for its antiemetic, appetite-stimulating, and muscle-relaxing effects. It also has side effects, such as cognitive changes, anxiety, paranoia. Other minor phytocannabinoids include cannabigerol (CBG), considered the “precursor” to THC and CBD, with antibacterial and analgesic effects; cannabichromene (CBC) with anti-inflammatory and analgesic properties; and tetrahydrocannabivarin (THCV), which produces effects similar to THC but milder; in some research, it has been studied for its potential to control appetite (Table I).

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Figure 1.

Synthetic cannabinoids (psychoactive compounds).

Synthetic cannabinoids (SCBs) include JWH-018, HU-210, HU-331, SR144528, WIN 55,212-2, UR-144, and JWH-133, but more than 140 have been classified in this group. There are four main groups: aminoalkylindoles, classical cannabinoids, non-classical cannabinoids, and fatty acid amides (12). SCBs can cause cell death by apoptosis, and they are associated with more serious adverse effects, and they are more addictive than the phyto-cannabinoids drugs (13) (Figure 1).

Psychotropic effects include increased relaxation, elevated well-being, and social disinhibition. Adverse events are several and may affect the central nervous system, liver, pulmonary system, kidneys, skin, cardiovascular system, muscles, and eyes (14).

Finally, there are the endocannabinoids, which are produced naturally by the human body. The “classical” components of the endogenous cannabinoid system are the endocannabinoids N-arachidonoyl ethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), along with the cannabinoid receptors CB1 and CB2. These receptors are activated by cannabinoid ligands. CB1 receptors are predominantly found in the central nervous system, where they regulate neurotransmitter release, particularly via GABAergic neurons. CB1 receptors are abundant in the cerebral cortex, basal ganglia, hippocampus, and cerebellum, and they also exist on plasma membranes, endosomes, and mitochondria, where they help regulate neuronal energy metabolism. Astrocytes, oligodendrocytes, and their precursors also express CB1 receptors, influencing cognitive functions like working memory (15, 16). Of significant clinical relevance, CB1 receptors in peripheral tissues–including the heart, lungs, liver, and reproductive organs–play key roles in gastrointestinal motility, energy balance, reproduction, pain regulation, and muscle metabolism. Additionally, CB1 and CB2 receptors are expressed in human immune tissues and leukocyte subpopulations (17, 18). CB2 receptors, are mainly found in immune regulatory tissues such as B cells and natural killer cells. These receptors play a crucial role in modulating inflammatory responses and are being explored as potential therapeutic targets, as CB2 agonists can produce pain-relieving effects without the psychoactive side effects associated with CB1 activation. Unlike CB1, CB2 also helps reduce the production of reactive oxygen species (19). In addition to CB1 and CB2, endocannabinoids interact with other receptors and channels, including transient receptor potential (TRP) channels, GPCRs like GPR55, GPR18, and GPR119, as well as GABA-A receptors, glycine receptors, adenosine receptor, dopamine receptor, and nuclear receptors such as peroxisome proliferator-activated receptor gamma (PPAR-γ) (20, 21) (Figure 2). Some studies suggest that the activation of CB1 receptors may translate into an antitumor activity as it causes: cell cycle arrest, cell growth inhibition, metastasis inhibition and apoptosis (22).

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Figure 2.

Cannabinoid receptors.

We can also recognize other compounds, like Terpenes, which are aromatic compounds found in many plants, including cannabis. Chemically, terpenes are compounds derived from the isoprene unit (C5H8) and can be classified into different categories based on the number of these units in their structure. Although not psychoactive, terpenes influence the effectiveness of cannabinoids through the entourage effect, a synergy that amplifies their overall effects. The main terpene is Myrcene, one of the most common terpenes in cannabis. It has an earthy, musky, clove-like aroma and is thought to contribute to the sedative effects of cannabis. It has a sedative and analgesic effect. Limonene is known for its citrus aroma and potential antidepressant and anxiolytic effects. Limonene has been observed to improve mood and reduce stress. Linalool, also found in lavender, is associated with relaxing and anti-inflammatory properties. It is often used in aromatherapy to reduce anxiety and improve sleep quality. Pinene has a pine-like aroma and is known for its anti-inflammatory and bronchodilator properties. It may also help counteract the memory loss effects associated with THC. Flavonoids are a class of antioxidant compounds found in many plants, including cannabis. From a chemical point of view, flavonoids have a basic structure of 15 carbon atoms (C6-C3-C6), characterized by two aromatic rings (A and B) linked by a three-carbon chain that often forms an oxygenated ring (C). Approximately 20 flavonoids have been identified in cannabis, some of which are unique to this plant. Flavonoids are categorized into six primary subclasses based on their chemical structure: Flavonols, found in onions and apples, such as quercetin and Kaempferol; Flavones, present in parsley and celery, such as Apigenin, Luteolin; Flavanones, mainly from citrus fruits, such as Naringenin, Hesperidin; Isoflavones, found in soy and legumes, such as Genistein, Daidzein; Flavanols (Catechins), abundant in green tea and chocolate, such as Catechin, epigallocatechin gallate; and Anthocyanins, responsible for blue, red, and purple colors in fruits and vegetables, such as Cyanidin. This classification allows us to understand the functional diversity of flavonoids and the various biological activities they can exhibit, like antioxidant and anti-inflammatory activities (23). Cannaflavins (A, B, C) are flavonoids unique to cannabis with potent anti-inflammatory properties. Cannaflavin A has been studied for its therapeutic potential against chronic inflammation (24-28). Table II lists the terpenes and flavonoids in cannabis and their effects.

Bioavailability of Cannabis

Bioavailability is the fraction (%) of the administered drug which reaches the bloodstream. Bioavailability of cannabis plays a crucial role in therapeutic outcome, as the onset times, duration and intensity of the pharmacological effect vary according to the route of administration (29).

Healthcare providers and patients should consider these factors when selecting the appropriate route of administration of cannabis for medical purposes. The possible routes of administration for medical cannabis include the following:

• i) Inhalation (smoking and vaporization).

  When cannabis is smoked, THC and CBD are rapidly absorbed through the lungs. The bioavailability of THC via smoking ranges from 10% to 35%, depending on factors such as how deeply and how long the smoke is inhaled. Peak plasma levels are generally reached within 6 to 10 min after inhalation. Vaporizing cannabis involves heating the plant material or extract to a temperature that releases cannabinoids without combustion. This method provides a bioavailability of approximately 30% to 60%, with peak effects occurring within minutes (30).

• ii) Oral ingestion.

  This route is characterized by a delayed onset of effects (1 to 2 hours post-ingestion) due to the digestive process and first-pass metabolism in the liver, a phenomenon that occurs whenever a drug is administered orally and reduces its bioavailability. The bioavailability of orally ingested THC is approximately 4% to 12%, while CBD’s oral bioavailability is approximately 6%. In addition, other factors, such as gastric contents and individual metabolism, can influence absorption (31).

• iii) Sublingual and oromucosal administration.

  The Administration of cannabis sublingually (under the tongue) or buccally (inside the cheek) offers a faster onset of effects, typically within 15 to 45 min, and a bioavailability ranging from 12% to 35% for CBD (32).

• iv) Rectal administration.

  Administration of cannabis through the rectal route (often in the form of suppositories) allows higher bioavailability than oral ingestion due to reduced first-pass metabolism. THC-hemisuccinate suppositories have demonstrated bioavailability of approximately 13.5% in animal studies (31).

• v) Transdermal application.

  Transdermal patches administer cannabinoids through the skin directly into the bloodstream, providing a consistent release over time. However, the bioavailability of transdermally applied cannabinoids is generally low as absorption may be hindered and discontinuous (33).

• vi) Intranasal administration.

  This method delivers cannabinoids directly into the nasal cavity using a spray, allowing for rapid absorption through the mucous membranes. The bioavailability of cannabinoids administered intranasally varies based on the specific compound and formulation used (34).

Clinical Use in Head and Neck Cancers

Head and neck cancers are characterized by a distinct set of symptoms that vary depending on the location and stage of the disease. Moreover, these cancers often involve aggressive therapies such as surgery, radiotherapy, and chemotherapy, which can cause significant side effects that impair quality of life. Cannabinoids are especially beneficial in the management of head and neck cancers due to the complex symptom burden and the limitations of conventional treatments. Potential use of cannabinoids includes pain management, nausea and vomiting, cachexia and anorexia, anxiety and depression, dysphagia, and xerostomia.

• i) Pain management.

  Cancer-related pain, including mucositis (painful inflammation of the mucous membranes), can be debilitating. Post-surgical pain and pain from metastasis to the bones or nerves add to the burden (35). Chronic pain is one of the most distressing symptoms for patients with head and neck cancer. Traditional analgesics, including opioids, often fail to provide adequate relief or come with a significant burden of side effects such as sedation and constipation. Medical cannabis, particularly THC, has been shown to reduce cancer pain by acting on the cannabinoid receptors (CB1) in the brain and spinal cord, modulating pain perception. In combination with conventional pain medications, cannabis has a synergistic effect, potentially reducing the required dose of opioids and mitigating the risk of opioid-related adverse effects (36, 37). Furthermore, an interesting feature of cannabidiol is the negative allosteric modulation of the μ opioid receptor (MOR), which is involved in the control of opioid drug abuse and relapse (38).

  Table III presents the types of pain commonly associated with head and neck cancer and how cannabis may help manage each type.

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  Table III.

  This table highlights how cannabis may address different pain types commonly found in head and neck cancer patients.

• ii) Nausea and vomiting.

  The side effects of chemotherapy or radiation severely impact a patient’s ability to maintain nutrition and hydration. One of the best-established uses of medical cannabis is its antiemetic properties. Both THC and CBD have been shown to reduce nausea and vomiting. In particular, THC works by binding to CB1 receptors in the brain and gut areas involved in the regulation of nausea and vomiting. CBD is not as effective on nausea as THC; it has been shown to help by reducing anxiety, which can sometimes worsen nausea, and by modulating the gastrointestinal system (6).

  Cannabis can help patients with head and neck cancer to tolerate chemotherapy better, maintain their nutritional status, and prevent dehydration (39).

• iii) Cachexia and anorexia.

  Many patients experience weight loss due to a combination of reduced appetite, swallowing difficulties, and increased metabolic demands of the tumor. The anorectic effects of head and neck cancers, compounded by treatment side effects, can lead to profound weight loss and cachexia, which negatively affects patient survival and quality of life (40). Medical cannabis, particularly formulations high in THC, has appetite-stimulating properties, commonly referred to as “the munchies”. Specifically, THC activates the CB1 receptors in the brain, which are involved in regulating appetite and food intake, and CBD (although not directly stimulating appetite like THC) has anti-inflammatory and anti-anxiety properties, which may be beneficial in reducing symptoms that exacerbate cachexia and anorexia, such as pain and psychological distress. Therefore, by improving food intake, medical cannabis helps to counteract weight loss and promote energy balance in patients with cancer (41).

• iv) Anxiety and depression.

  The psychological impact of a head and neck cancer diagnosis, disfigurement, and treatment side effects contribute to anxiety and depression. Anxiety and depression are common among patients with cancer, particularly those with head and neck cancers due to the visible and functional impairments caused by the disease and its treatment. Furthermore, some studies suggest that cannabis use can improve sleep quality, another critical factor in the holistic management of patients with cancer.

  Cannabis may help with anxiety and depression in head and neck cancer through the following mechanisms:

  Anxiolytic effects. Studies suggest that cannabis, particularly CBD, may help reduce anxiety in some patients. It is thought to interact with the brain’s endocannabinoid system, which regulates mood and stress responses (42).

  Antidepressant effects. Some studies suggest that cannabis (especially CBD) may have mild antidepressant-like effects by modulating serotonin levels, a key neurotransmitter involved in mood regulation. By enhancing mood and reducing stress, it can improve patients’ emotional well-being.

  Pain management. Chronic pain is common in patients with head and neck cancer, and both THC and CBD are well-known for their pain-relieving properties. By reducing pain, cannabis may indirectly help alleviate symptoms of anxiety and depression that stem from physical discomfort (43).

  Sleep improvement. Both THC and CBD have shown potential in improving sleep quality. Since poor sleep is a common issue among people with cancer and those suffering from anxiety or depression, better sleep could positively affect their mental health. However, it is important to note that THC’s effects on sleep are dose-dependent. While low doses may reduce sleep onset latency and increase slow-wave sleep, high doses can cause sleep disturbances (44).

• v) Dysphagia and xerostomia.

  Radiation therapy to the head and neck often results in dry mouth and difficulty swallowing, further impairing the patient’s ability to eat and drink. Dry mouth and difficulty swallowing are particularly challenging for patients with head and neck cancer, especially those receiving radiation therapy (45). While direct evidence on cannabis’s role in alleviating xerostomia is limited, cannabinoids’ ability to reduce inflammation and modulate pain may offer indirect benefits for patients struggling with oral discomfort and mucositis. Particularly THC and CBD, may help alleviate symptoms in certain cases.

  Muscle relaxation. THC has been shown to relax muscles, which could help ease the difficulty in swallowing by reducing spasms or tightening of the throat.

  Pain management. Dysphagia often comes with pain, especially when caused by head and neck cancer or its treatments. THC is known for its analgesic (pain-relieving) effects, which may help in reducing discomfort associated with swallowing. While the direct impact of cannabis on dysphagia is not yet fully studied, research into cannabinoids for muscle relaxation and pain control in related conditions (such as esophageal cancer) is promising (46). Regarding Xerostomia, some anecdotal evidence suggests that cannabis may help stimulate salivary flow, though more research is needed in this area (47).

  Saliva stimulation. THC and CBD may stimulate the endocannabinoid receptors involved in the regulation of saliva production. Some studies suggest that cannabinoids might enhance salivation, which could counteract the effects of xerostomia (47).

  Pain relief and comfort. For those with cancer treatments affecting the salivary glands, the analgesic effects of THC can help alleviate dry mouth’s associated discomfort, improving the overall quality of life. However, while cannabinoids may provide relief, they may also have a paradoxical effect on some individuals by causing dry mouth owing to the way THC interacts with the body. This necessitates further studies to understand the full scope of cannabis’ impact on xerostomia (47).

Safety Considerations and Challenges

The use of medical cannabis as part of supportive care in patients with head and neck cancer has been gaining attention due to its potential benefits in managing symptoms such as pain, nausea, anxiety, and loss of appetite, which are common in these patients. Head and neck cancers often involve treatments like surgery, radiotherapy, and chemotherapy, which can result in significant side effects, making symptom control a key component of patient care.

Studies have shown that cannabis, particularly its active components THC and CBD, may help alleviate cancer symptoms. For instance, medical cannabis has been used effectively to manage pain and reduce the use of opioids, a common pain management approach with many side effects. A study noted that some patients with cancer were able to significantly reduce their opioid intake by using cannabis, thus minimizing opioid-related complications like constipation and respiratory depression.

While medical cannabis has shown promise, its use in cancer care comes with safety considerations. Common side effects of THC include drowsiness, euphoria, xerostomia and impaired cognitive function, which may be undesirable for some patients. CBD, which is generally well-tolerated, can have side effects such as fatigue, diarrhea, and changes in appetite, but it is less likely to cause the psychoactive effects of THC. Dose titration is essential to balance therapeutic benefits with minimal side effects. Long-term use of cannabis, particularly in high doses, has been associated with tolerance and dependency, although these risks are considered lower than those associated with opioids. Another aspect to consider concerns drug interactions, especially for patients who are on multiple medications (e.g., opioids, antidepressants, or chemotherapy agents). Cannabis can interact with enzymes in the liver, potentially altering the metabolism of other drugs.

Another challenge is the variability in the quality and concentration of cannabis products, especially in regions where cannabis is not standardized or well-regulated. The method of administration also matters—smoking cannabis, for example, may exacerbate respiratory symptoms, particularly in patients undergoing radiation therapy. Inhalation via vaporization or oral administration (oils, capsules) may offer safer alternatives. Further clinical trials are necessary to establish standardized dosing guidelines for cannabis use in patients with head and neck cancer. The main types of approved cannabinoids are summarized in Table IV. In Italy, cannabis extracts in MCT oil containing THC and/or CBD are regulated for use in compounded preparations (magistral preparations) with clearly defined therapeutic indications and legal requirements, as outlined in AIFA Determinations DD 194/2023 and DD 337/2024 (Table V). Ongoing clinical trials investigating the role of cannabinoids in cancer care are presented in Table VI.