Continuing Education Activity

There are currently three cannabinoids available on the pharmaceutical market. Dronabinol and nabilone are both synthetic tetrahydrocannabinol (THC) which the FDA has approved for the treatment of chemotherapy-induced nausea and vomiting (CINV) after the failure of a trial of first-line anti-emetics. Both are also FDA-approved to treat anorexia associated with AIDS. Recently, the FDA has also approved a cannabidiol (CBD) product to treat seizures associated with Lennox-Gastaut syndrome and Dravel syndrome in pediatric patients. However, there is no FDA-approved indication for its use as an anti-emetic. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of cannabinoid antiemetics, pertinent for clinicians and other interprofessional team members to ensure the appropriate utilization of these drugs.

Objectives:

• Identify the indications, both approved and off-label, of cannabis-based antiemetics.
• Review the mechanism of action of cannabis-based antiemetics.
• Outline the potential adverse effects of cannabinoid antiemetics.
• Summarize the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with the cannabinoid antiemetic class of medications.

Indications

There are currently three cannabinoids available on the pharmaceutical market. Dronabinol and Nabilone are both synthetic tetrahydrocannabinol (THC), which the FDA has approved for the treatment of chemotherapy-induced nausea and vomiting (CINV) after the failure of a trial of first-line anti-emetics. Both are also FDA-approved to treat anorexia associated with AIDS.  Recently, the FDA has also approved a cannabidiol (CBD) product to treat seizures associated with Lennox-Gastaut syndrome and Dravel syndrome in pediatric patients. However, there is no FDA-approved indication for its use as an anti-emetic.[1] Independently produced cannabidiol extracts are being used increasingly in the general population for many non-FDA-approved indications, frequently including nausea and emesis.  In states that have decriminalized marijuana, both in recreational and medicinal contexts, products with varying ratios of cannabidiol and THC are also used for their anti-emetic properties.[1]

Mechanism of Action

Cannabinoids and their anti-emetic potential are still under research, and many of the intricacies behind their mechanisms are still unknown or lack universal consensus.  Cannabinoids exert their anti-emetic properties through interactions with the centrally located CB1 receptors and 5-HT3 receptors in the dorsal vagal complex (DVC), which mediates emesis. A significant contributor to emesis appears to be via activation of 5-HT3 receptors in the DVC, specifically in the area postrema. Studies in animal models have shown that anandamide, an endogenous cannabinoid, THC, and several synthetic cannabinoids have demonstrated allosteric inhibitor effects on the 5-HT3 receptors in the DVC, providing a mechanism through which emesis control occurs.  Animal models have also shown that cannabinoids may work on pre-synaptic CB1to decrease the release of serotonin into the synapse, thus inhibiting the nausea/emetic response.  

Animal models have also indicated CBD to have an allosteric inhibitory effect on the 5-HT3 receptor. However, this effect may be mainly through its activation of the 5-HT1A receptor. The activation of the 5-HT1A receptor ultimately reduces the amount of serotonin released, and thus a lower potential to trigger emesis. CBD is also thought to activate the CB1 receptors in the gastrointestinal tract through their G-protein-coupled receptor inhibitory effect, leading to decreased gastrointestinal motility. THC and CBD were once credited with inhibiting fatty acid amide hydrolase (FAAH), leading to an increased concentration of anandamide that could exert its anti-emetic properties at a higher intensity, but recent studies into this mechanism have been equivocal.[2]

Administration

Dronabinol dosing can be via either oral pill and oral solution forms, available in doses of 2.5 mg, 5 mg, and 10 mg. In CINV, the patients should take it 1 to 3 hours before starting their chemotherapy session, with a repeat dose available 2 to 4 hours after beginning the session as needed. Nabilone is available in oral pill form, in doses of 1 mg or 2 mg. These doses can be increased or decreased based on practitioner discretion. Patients should receive instruction to take one dose the night before starting their chemotherapy session, one dose twice a day during the entirety of the chemotherapy course, and one dose twice a day after chemotherapy has concluded. CBD is sold legally throughout the United States without a prescription by many private entities that are not FDA regulated; there are no concrete guidelines for dosing. However, doses generally range from 10 mg to 50 mg at a time, taken either as needed or daily.  Products containing significant THC levels are sold legally by medicinal and recreational dispensaries in several states, depending on legal status. Doses for these generally range between 5 mg and 15 mg and are typically taken as needed as opposed to daily due to their psychotropic effects.[1][3]

Adverse Effects

Adverse effects depend on the cannabinoid administered. The most common adverse effects of formulas containing a THC component are acute intoxication, tachycardia, aboulia, and psychosis. Psychoses manifest most commonly as perceptual alteration but also frequently include panic attacks, anxiety, paranoia, and depression.[4] Individuals using THC-containing cannabinoid products chronically and at a high volume are also at risk of developing cannabis hyperemesis syndrome, which can present as intractable nausea and vomiting.[5] Cannabinoid formulas containing only a CBD component have less potential to cause behavioral side effects, although drowsiness occurs frequently. CBD is a CYP3A4 inhibitor, potentially leading to drug interactions and toxicities in molecules metabolized by the CYP3A4 system.[6] In vitro studies have shown an association between CBD and reduced fertility and alterations of cell viability. Dronabinol has reported adverse effects of gastrointestinal upset, dizziness, paranoia, somnolence, and abnormal thoughts.[7] Nabilone has reported adverse effects that include acute intoxication, ataxia, headache, drowsiness, and deficits in concentration.[8]

Contraindications

Cannabinoids are contraindicated in individuals with a history of hypersensitivity reactions that can be related to any form of cannabinoid consumption. They should be used cautiously in patients who have experienced intolerable side effects in the past. Dronabinol is specifically contraindicated in patients with hypersensitivity to sesame oil.[7]

Monitoring

Monitoring depends on the clinical manifestation of the patient, as there are no streamlined laboratory procedures that can measure cannabinoid serum levels. The monitoring of patients receiving cannabinoids should include checking for tachycardia, orthostasis, and behavioral changes.[9] Use by patients with a history of cannabis use disorder should undergo close scrutiny, as the potential of cannabinoid use disorder relapse in such individuals is high.[10] Precautions in patients with hepatic or renal dysfunction are as yet not investigated. Coadministration with CYP inhibitors may lead to toxicity, and concurrent administration with CYP inducers may result in lower efficacy.[11]

Toxicity

There is not much data on the toxicities of cannabinoids in the literature. The lethal dose 50 (LD50) is as yet undetermined, and both dog and monkey models have shown that doses up to 3000 mg/kg do not lead to fatality.[4] There is no antidote; only supportive therapy is available for cannabinoid overdose. Chronic, prolonged, high volume use of cannabinoids can lead to neuropsychiatric effects, with IQ and cognition being most impacted.[12] The toxic dose reported for dronabinol is estimated to be at 30 mg/kg. Illicit synthetic cannabinoids are known to lead to toxicity at much lower doses.

Enhancing Healthcare Team Outcomes

Opinions and values regarding cannabinoids in medicine vary by individual. They can range from seeing the great potential to ease suffering to believing molecules derived from cannabis have no place in modern medicine.  Regardless of personal values, healthcare providers should recognize the existence and use of cannabinoids among their patient population and consider this when deciding on treatment options. Patients should feel comfortable telling their provider if and how they use cannabinoids and the type (CBD:THC ratio). Dronabinol and nabilone are both legal throughout and are available by prescription in all 50 states.[1][13] The legality regarding formulas that contain only CBD is more variable. (These products are available legally throughout all 50 states.) Laws are much more variable between the states concerning restricting products with THC components.[1] If a patient reports to the medical staff using a cannabinoid, that information should ultimately be relayed to the primary clinician overseeing their care.  

Using cannabinoids for emetic control is best accomplished with an interprofessional healthcare team model. The primary specialties that are prescribing dronabinol and nabilone are oncology, palliative care, and infectious diseases. Oncology providers will often order simultaneous treatment with a cannabinoid alongside chemotherapy regimens.[14] Palliative care and infectious disease providers will often order cannabinoids to provide comfort in the setting of nausea or to capitalize on their orexigenic components. Providers, including nurse practitioners, physician assistants, and physicians from varying specialties, can order permission for patients with a variety of ailments, including nausea and vomiting, to obtain and use CBD and THC-containing formulas in states with legal, medical marijuana. Providers from many specialties have also recommended over-the-counter CBD-only products to their patients for numerous indications, including nausea and vomiting. The research behind the potential of cannabinoids in medicine is still in its initial phases, and much of the biomedical applications researched are reliant on recent animal models and anecdotal cases. Pharmacists can verify dosing, check for potential interactions, and provide additional patient counseling if necessary. It is essential to consider the entire clinical picture when deciding whether to initiate cannabinoid therapy, and an interprofessional team approach is the optimal means to achieve this goal. [Level 5]