Continuing Education Activity

THC or Tetrahydrocannabinol is the major psychoactive component and one of the 113 cannabinoids recognized in cannabis. A synthetic formulation of THC, dronabinol, is FDA approved to manage chemotherapy-induced nausea and vomiting and for appetite stimulation in HIV/AIDS anorexia. Another synthetic THC, nabilone, is FDA approved for use in chemotherapy-induced nausea and vomiting. Aside from these two synthetic THC formulations of THC that are FDA approved. Cannabis and, therefore, THC, which is the major psychoactive component, is legal in several states and used by several patients for medical and recreational purposes. However, FDA classifies cannabis under Schedule 1, and thus its use is forbidden in any products. This activity will highlight the indications, contraindications, off-label uses, pharmacodynamics, and adverse events in the use of THC synthetic analogs for interprofessional team members managing the care of patients with chemotherapy-induced nausea and vomiting or AIDS-related anorexia.

Objectives:

• Review the indications and off-label uses of THC and its analogs in a clinical setting.
• Describe the mechanism of action of THC for cancer-related nausea.
• Outline the administration of THC use for cancer-related nausea.
• Summarize how interprofessional teamwork can improve patient outcomes when using THC for cancer-related nausea.

Indications

Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive cannabinoid extracted from the cannabis (marijuana) plant. It was historically used recreationally due to its psychoactive effects, but recently there has been significant interest in exploring its medical utility.

Synthetic THC, such as nabilone and dronabinol, are FDA approved for chemotherapy-induced nausea and vomiting. Dronabinol is also FDA approved for HIV/AIDS anorexia for appetite stimulation.[1][2] These two drugs are the only synthetic THC formulations that are FDA approved in the US, though the use of cannabis for several off-label and medical uses has picked up as several states in the United States have legalized the use of cannabis. 

Many states permit medical marijuana use, though it continues to be a Schedule 1 drug with no currently accepted medical use and at high risk for abuse by Federal standards.  Per the American Society of Clinical Oncology 2017 guidelines, there is insufficient evidence to recommend THC as monotherapy for chemotherapy-induced nausea and vomiting. Although for breakthrough nausea and vomiting refractory to ondansetron, there is moderate evidence for the utility of THC if used alongside standard antiemetic therapy.[3] 

Currently, various possible off-label uses of THC are objects of active research. Randomized controlled trials have shown that synthetic THC-dronabinol improved respiratory stability in patients with moderate to severe obstructive sleep apnea (OSA).[4] However, further research is still necessary regarding its tolerability, safety profile, and long-term use. Thus, it is not currently recommended by the American Academy of Sleep Medicine for use in OSA.[5]

Randomized control trials have also shown THC to effectively improve fibromyalgia and chronic neuropathic pain, though its off-label use is still controversial and requires further research.[6][7] 

Even though synthetic cannabinoids dronabinol and nabilone are FDA approved for chemotherapy-induced nausea and vomiting, research has not found it an effective antiemetic for postoperative nausea and vomiting.[8] Currently, cannabis is legal for medical purposes in over 50% of the states, and seventeen states permit products that are high in cannabidiol (CBD) and low in THC (tetrahydrocannabinol) for medical use.[9] Although cannabis is legal for medical purposes in several states, its use is prohibited in any product by the Food and Drug Administration, preventing its distribution, limiting clinical research, and restricting other therapeutic applications.[9]

Mechanism of Action

THC binds to cannabinoid receptors CB1 and CB2, which are part of the endogenous cannabinoid system. THC binds primarily to CB1 receptors though there is a weak binding of CB2 receptors. The expression and pathway of these receptors are still the focus of research; however, it is known that CB1 receptors predominantly express in the central nervous system(CNS), while CB2 receptors are expressed in the peripheral nervous system(PNS) immune cells and organs.[10][11] 

THC’s effects on emesis, appetite, and pain are attributed to its binding of CB1 receptors in the CNS, through which it modulates sensory, somatic, and cognitive perception.[3][2][6] Regarding its possible benefits in OSA, THC appears to be an antagonist of serotonin in the PNS.[4] Serotonin is involved in controlling respiration, and its dysregulation has implications in disordered breathing during sleep.[12]

Administration

There are two FDA-approved synthetic THC compounds.

Nabilone is typically available as a PO capsule of 1 mg. 

Refractory nausea and vomiting due to cancer chemotherapy: initial dosing of nabilone begins at 1 to 2 mg twice daily. Dosing continues for up to 48 hours after the last chemotherapy treatment. The maximum dose is 2mg TID.[13]

Dronabinol is available in two forms. Either in a PO capsule of 2.5 mg, 5 mg, and 10 mg or a PO solution of 5 mg/ml with a calibrated syringe.

For anorexia in patients with AIDS: an initial dose of 2.5 mg twice daily is recommended, one hour before lunch and dinner with a maximum dose of 10 mg/day.

Refractory nausea and vomiting due to cancer chemotherapy: for both capsule and oral solution, an initial dose of 5 mg should be given 1 to 3 hours before initiating chemotherapy and then every 2 to 4 hours after chemotherapy, with a total of 4 to 6 doses administered daily. Initial dosing ideally occurs after fasting for 10 hours and at least 30 minutes before eating. The administration of subsequent doses does not need to be with regard to meals. The maximum dosage is 15 mg per dose, with 4 to 6 doses per day.[14]

Adverse Effects

The most commonly reported side effects of THC that require its discontinuation are dysphoria, hallucinations, and paranoia. Other common side effects include sedation, confusion, headache, dry mouth, dysphoria, euphoria, and hypotension. Seizures and seizure-like activity have been known to occur in patients using THC.[15][16]  

There has been an increasing number of case reports of cannabinoid-induced hyperemesis syndrome as the use of cannabis has become more widespread. Such a syndrome is characterized by intractable vomiting from chronic THC use. A characteristic feature of this syndrome is relief with hot showers.[17]

Another side effect or complication from chronic cannabis use is an amotivational syndrome, which clinically resembles depression with a lack of motivation.

Multiple studies have linked marijuana use to increased risk for psychiatric conditions, including psychosis, depression, anxiety, schizophrenia, and substance use disorders.

Contraindications

Contraindications for dronabinol and nabilone are hypersensitivity to cannabinoids or components of its formulation. For dronabinol, this includes sesame for the capsule formulation and alcohol for the oral solution. Care is necessary for elderly patients due to the increased risk of postural hypotension and cannabis-induced delirium. Dronabinol is listed as a pregnancy Category C drug as it has not demonstrated any teratogenic effects in animal models at 0.2 to 5 times the maximum recommended human dose, but there have been no well-controlled studies in pregnant women.[13] Nabilone is also listed as a Pregnancy Category C drug. Therefore, clinicians should avoid these medications in pregnant or nursing mothers.[14]

Monitoring

Physicians should assess for psychiatric or cognitive impairment associated with THC use and be aware of interactions with drugs of similar effects. Hemodynamic changes also require monitoring after administration. Patients should be informed not to operate motor vehicles or heavy machinery until reasonably certain they are not impaired by THC. The risk of dependence and misuse must also be assessed, especially in patients with a history of substance abuse or dependence. As seizures or seizure-like activity has occurred in patients using THC, care is necessary when prescribing to patients with risk factors or a history of seizures, including those taking anti-epileptic medication.[18]

Toxicity

Currently, there is no known toxic dose of THC. For cases of marijuana intoxication, treatment is supportive and symptomatic management.[19] In the event a patient develops cannabinoid-induced hyperemesis syndrome, management involves cessation of cannabis use.[17]

Enhancing Healthcare Team Outcomes

Patients must be carefully selected when prescribing THC formulations approved by the FDA for medical use. Due to the sedation and euphoria effects of THC, physicians should consider a history of drug abuse or dependency and polypharmacy. Furthermore, the psychoactive effects of THC, such as hallucinations, dysphoria, and paranoia, are intolerable to some patients.[15][16] Thus, multi-disciplinary management of such patients is required, including psychiatrists, addiction specialists, and nurses, to screen for possible drug abuse or adverse effects or treatment of THC-induced psychiatric and medical concerns. Furthermore, prescribers and pharmacists must be aware of the complex legal framework surrounding the use of THC for medical purposes. As of 2020, THC has been legalized for medical use in over half of the states in America, and several states also allow for its recreational use.[20] 

However, the legal status of THC is constantly in flux. Marijuana is federally classified as a class I scheduled drug, and there is no federally recognized use of medical marijuana. Even so, no formal legal decision has addressed this inconsistency between state and federal law. Thus, healthcare providers must stay up to date about specific state and federal regulations to protect both the patient and the prescriber.[21] Currently, synthetic THC is FDA approved for AIDS-related anorexia and chemotherapy-induced nausea and vomiting. Certain chemotherapy regimens that include cyclophosphamide, methotrexate, and fluorouracil are known to be emetogenic. The FDA-approved THC formulations are helpful in the treatment of chemotherapy-induced nausea and vomiting.

Randomized clinical trials have shown that THC was more efficacious in patients given these chemotherapy agents than other second-line antiemetics such as prochlorperazine and metoclopramide. However, with highly emetogenic chemotherapy regimens such as high-dose methotrexate, cisplatin, or doxorubicin, THC was not more effective.[15] 

Furthermore, other potential uses of THC are being explored, and its off-label use may help manage some patients. The most promising research includes THC's use in the management of OSA and chronic neuropathic pain. Randomized control trials have shown that THC can be effective in improving OSA and chronic neuropathic pain. However, these studies were small in size with unclear results. As such further research is necessary on the tolerability and side effect profile of THC in treating these conditions.[5][6][7] 

As research grows, there is a good possibility that additional indications will be approved for medical use by the FDA. There must be a thorough discussion between the prescribing/ordering clinician and patient over the benefits and harms of THC. Additionally, interprofessional communication between all healthcare team members, including clinicians (MDs, DOs, NPs, PAs), specialists, nursing staff, and pharmacists, can help improve patient outcomes in patients who receive treatment with currently approved indications for THC formulations. Everyone on the interprofessional team needs to keep abreast of the latest data-driven evidence for these agents to properly assess their appropriateness for a given patient case.