Dronabinol is a synthetic form of tetrahydrocannabinol ('THC'), which obtained FDA approval in 1985 for the treatment of HIV/AIDs-induced anorexia and chemotherapy-induced nausea and vomiting ('CINV') in patients who do not successfully respond to conventional antiemetics. Dronabinol has also been used off-label for the treatment of OSA with mixed and unclear efficacy (only Phase II trials performed). Therefore, the American Academy of Sleep Medicine does not support its use until reliable data is available (such as Phase III trials). There are also recent studies utilizing dronabinol in chronic pain patients, which showed efficacy compared to placebo, but further research is necessary. Additionally, current fields exploring the use of dronabinol include substance abuse and withdrawal.
As such, the indications for this cannabinoid in adults are HIV/AIDs-induced anorexia and chemotherapy-induced nausea and vomiting in patients who do not successfully respond to conventional antiemetics.
Dronabinol is an orally active cannabinoid (a synthetic form of the active delta-9-tetrahydrocannabinol). The majority of effects of cannabinoids and endocannabinoids (endogenous cannabinoids) appear to be carried out by two inhibitory G-protein coupled-receptors (GPCRs), CB1 (present in high levels in several brain regions including the prefrontal cortex, hippocampus, amygdala, basal ganglia, and the cerebellum) and CB2 (present in a restricted distribution in the brain stem and periphery including immune cells and neurons).
When activated, CB1 generally reduces neuronal excitation. Dronabinol, like THC, is a partial agonist at the CB1 receptor. Cannabinoid signaling carries implications in many pathways, including pain modulation, cognition, appetite stimulation, anti-nausea, among others. The anti-emetic and appetite stimulation effects of the CB1 receptor appear to mediate the therapeutic effects of dronabinol.
Dronabinol is an orally active cannabinoid (a synthetic form of the active Delta-9-tetrahydrocannabinol) that is available in round, soft gelatin 2.5 mg (white), 5 mg (dark brown), and 10mg (orange) capsules. Dronabinol is insoluble in water. As such, it is formulated in sesame oil (providers must inquire about patient allergies). Dosing for specific therapy is outlined below:
The recommended starting adult dosage is 2.5 mg orally twice a day, one hour prior to lunch and dinner.
Dosing Considerations: Elderly patients may not be able to tolerate 2.5 mg twice daily. One may consider 2.5 mg once a day (later in the day may reduce unwanted CNS symptoms)) and titrate up to reduce unwanted CNS symptoms. The unwanted effects of feeling high, dizziness, confusion, and somnolence usually resolve in 1 to 3 days.
Titration and Maximum Dosage: Increase gradually to 2.5 mg 1 hour before lunch and 5 mg 1 hour before dinner. Most patients will receive the desired therapeutic effect with this dosage, but dosing can be increased slowly to a maximum of 10 mg twice daily.
Chemotherapy-induced nausea and vomiting ('CINV') in patients who have failed to respond to conventional antiemetics
The recommended starting adult dosage is 5 mg orally, which should be taken 1 hour or up to 3 hours before chemotherapy followed by 5 mg every 2 to 4 hours (4 to 6 total doses in a day). The initial dose should be on an empty stomach, which generally is greater than 30 minutes before a meal. The patient does not need to consider the timing of meals or food intake regarding subsequent doses after the first dose.
Dosing Considerations: Similar to dosing for anorexia, elderly patients may be started on a lower dose of 2.5 mg once daily before chemotherapy to reduce CNS symptoms.
Titration and Maximum Dosage: The drug can be titrated up in amounts of 2.5 mg. The maximum dose is 15 mg for each dose (4 to 6 total doses in a day).
Careful attention is necessary regarding the potential adverse effects of dronabinol as it is titrated. See the 'Adverse Effects' and 'Monitoring' sections for further details.
Hypersensitivity to Dronabinol or Sesame Oil: Clinical staff should monitor patients for signs of hypersensitivity reactions. Reported signs include lip swelling, hive, rash, oral lesions, skin burning, and throat tightness.
Other Adverse Effects: The most common adverse reactions (≥3%) include abdominal pain, dizziness, euphoria, nausea, paranoid reaction, somnolence, abnormal thinking, and vomiting. Please also see the 'Toxicity' section below.
Important Drug Interaction: Drugs that inhibit or induce cytochrome P450 2C9 and cytochrome P450 3A4 can affect the plasma concentration of dronabinol. Drugs that are typically highly-bound by protein in plasma can be displaced by dronabinol as it is a highly protein-bound drug (with higher affinity for carrier proteins than most others), increasing patient's exposure. Drugs with narrow therapeutic windows such as warfarin require close monitoring.
Other concerns include:
Dronabinol is formulated in sesame oil. As such, this drug is contraindicated in patients who have a history of hypersensitivity reaction to sesame oil or THC derivatives. Careful attention is necessary for signs of hypersensitivity reactions (see Monitoring below).
Metabolism: Liver via extensive first-pass, cytochrome P450 2C9, and cytochrome P450 3A4.
Onset of Action: Generally 0.5 to 1 hour.
Half-life: 4 hours.
Bioavailability:10 to 20%
Therapeutic Index (TI): TI is wide, and dosing is limited by adverse effects as a lethal dose of IV dronabinol is estimated at 30 mg/kg or greater. As such, max doses reflect increased rates of adverse effects. See the 'Administration' section for max doses.
Hypersensitivity to Dronabinol or Sesame Oil: Patients should be monitored for signs of hypersensitivity reactions. Reported signs include lip swelling, hive, rash, oral lesions, skin burning, and throat tightness.
Other Adverse Effects: The most common adverse reactions (which generally occur in greater than 3% but less than 10% of patients) include pain in the abdomen, nausea or vomiting, feelings of joy, feelings of paranoia, and abnormal thinking. Please also see the 'Toxicity' section below.
Important Drug Interaction: Drugs that inhibit or induce cytochrome P450 2C9 and cytochrome P450 3A4 can affect the plasma concentration of dronabinol. Drugs that are typically highly-bound by proteins in plasma can be displaced by dronabinol as it is a highly protein-bound drug (with higher affinity for carrier proteins than most others), increasing patient's exposure. Drugs with narrow therapeutic windows such as warfarin require close monitoring when co-administered with dronabinol.
The estimated lethal dose of IV dronabinol is 30 mg/kg (note this is for illustrative purposes as dronabinol dosing is oral). As such, the CNS toxicity (adverse CNS effects) of Dronabinol are more applicable for monitoring dose-limiting toxicity. Signs and symptoms of toxicity include:
Mild Intoxication: sleepiness, feelings of joy, heightened sensory vigilance, time perception difficulties, conjunctival injection, dry oral cavity, and elevated heart rate.
Moderate Intoxication: Memory difficulty, feelings of detachment, changes in mood, retention of urine, and decreased bowel motility.
Severe: Decreased coordination of motor function, lethargy, slurring of speech, and orthostatic hypotension.
Panic attacks in those with apprehension and seizures in those with a history of seizure can also occur.
Management of serious ingestion
There is no specific antidote for the treatment of dronabinol toxicity. If there is a history of recent serious ingestion, the patient should have gut decontaminated with activated charcoal (at a dosage of 30 to 100g for adults, 1 to 2 g/kg in infants). Delivery through a nasogastric tube may be necessary for an unconscious patient with a secure airway. Patients with intense psychiatric complications (such as depressive episodes, hallucinations, or psychosis) may need to be isolated in a quiet and peaceful area and frequently reassured by provider or staff. Benzodiazepines, such as diazepam (5 to 10 mg PO), can be utilized for extreme agitation. Hypotension is manageable with Trendelenburg positioning and isotonic IV hydration.
Managing anorexia associated with weight loss in patients with AIDs/HIV and nausea and vomiting that can accompany chemotherapy in patients who have not responded to traditional conventional antiemetics requires a team of healthcare professionals that may include nurses, palliative care specialists, pharmacists, oncology specialists and other physicians from other specialties.
Anorexia associated with weight loss in patients with AIDs/HIV
Level 1: Treatment of AIDs-related anorexia and weightloss was proven effective in a randomized, double-blind, placebo-controlled study with 139 patients. A statistically significant difference between dronabinol and placebo was observable in appetite. Additional measured trends included improved body weight and mood and decreases in nausea. Recent metanalyses have also shown dronabinol to be efficacious.
Nausea and vomiting associated with chemotherapy in patients who have not responded to traditional conventional antiemetic
Level 1: Treatment of chemotherapy-induced nausea and vomiting ('CINV') with dronabinol has been extensively studied as monotherapy and combined with other more traditional antiemetics such as ondansetron. Recent metanalyses have also shown dronabinol to be efficacious.
|||Carley DW,Prasad B,Reid KJ,Malkani R,Attarian H,Abbott SM,Vern B,Xie H,Yuan C,Zee PC, Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea. Sleep. 2018 Jan 1; [PubMed PMID: 29121334]|
|||Schimrigk S,Marziniak M,Neubauer C,Kugler EM,Werner G,Abramov-Sommariva D, Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients. European neurology. 2017; [PubMed PMID: 29073592]|
|||Levin FR,Mariani JJ,Pavlicova M,Brooks D,Glass A,Mahony A,Nunes EV,Bisaga A,Dakwar E,Carpenter KM,Sullivan MA,Choi JC, Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial. Drug and alcohol dependence. 2016 Feb 1; [PubMed PMID: 26711160]|
|||Badowski ME,Yanful PK, Dronabinol oral solution in the management of anorexia and weight loss in AIDS and cancer. Therapeutics and clinical risk management. 2018; [PubMed PMID: 29670357]|
|||May MB,Glode AE, Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics. Cancer management and research. 2016; [PubMed PMID: 27274310]|
|||Morales P,Jagerovic N, Novel approaches and current challenges with targeting the endocannabinoid system. Expert opinion on drug discovery. 2020 Apr 27; [PubMed PMID: 32336154]|
|||Reuter SE,Martin JH, Pharmacokinetics of Cannabis in Cancer Cachexia-Anorexia Syndrome. Clinical pharmacokinetics. 2016 Jul; [PubMed PMID: 26883879]|
|||Badowski ME, A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and pharmacodynamics. Cancer chemotherapy and pharmacology. 2017 Sep; [PubMed PMID: 28780725]|
|||Natale JJ, Reviewing current and emerging antiemetics for chemotherapy-induced nausea and vomiting prophylaxis. Hospital practice (1995). 2015; [PubMed PMID: 26308912]|
|||Bar-Sela G,Zalman D,Semenysty V,Ballan E, The Effects of Dosage-Controlled Cannabis Capsules on Cancer-Related Cachexia and Anorexia Syndrome in Advanced Cancer Patients: Pilot Study. Integrative cancer therapies. 2019 Jan-Dec; [PubMed PMID: 31595793]|
|||Badowski ME,Perez SE, Clinical utility of dronabinol in the treatment of weight loss associated with HIV and AIDS. HIV/AIDS (Auckland, N.Z.). 2016; [PubMed PMID: 26929669]|
|||Häuser W,Welsch P,Klose P,Radbruch L,Fitzcharles MA, Efficacy, tolerability and safety of cannabis-based medicines for cancer pain : A systematic review with meta-analysis of randomised controlled trials. Schmerz (Berlin, Germany). 2019 Oct; [PubMed PMID: 31073761]|
|||Mücke M,Weier M,Carter C,Copeland J,Degenhardt L,Cuhls H,Radbruch L,Häuser W,Conrad R, Systematic review and meta-analysis of cannabinoids in palliative medicine. Journal of cachexia, sarcopenia and muscle. 2018 Apr; [PubMed PMID: 29400010]|
|||Fisher E,Eccleston C,Degenhardt L,Finn DP,Finnerup NB,Gilron I,Haroutounian S,Krane E,Rice ASC,Rowbotham M,Wallace M,Moore RA, Cannabinoids, cannabis, and cannabis-based medicine for pain management: a protocol for an overview of systematic reviews and a systematic review of randomised controlled trials. Pain reports. 2019 May-Jun; [PubMed PMID: 31583356]|