Dronabinol

Dronabinol is a synthetic form of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis. It is marketed under brand names such as Syndros and is approved by the FDA for therapeutic use.

This medication is indicated for the treatment of chemotherapy-induced nausea and vomiting in patients who have not responded adequately to conventional antiemetic treatments. Dronabinol is also used as an appetite stimulant in patients with AIDS-related anorexia.

Dronabinol acts as an agonist at cannabinoid CB1 receptors in the central nervous system. Activation of these receptors modulates neurotransmitter release, producing antiemetic and appetite-stimulating effects.

The primary gene implicated in dronabinol metabolism is CYP2C9. CYP2C9 encodes a liver enzyme belonging to the cytochrome P450 family, which is responsible for breaking down dronabinol into inactive metabolites.

Variations in the CYP2C9 gene can alter enzyme activity. For example, certain alleles lead to reduced metabolic function, resulting in slower clearance of dronabinol. In contrast, normal-function alleles support typical drug metabolism and elimination.

Genetic variations in CYP2C9 classify patients into metabolizer phenotypes—normal, intermediate, or poor—which influence dronabinol blood levels. Poor metabolizers have reduced clearance, leading to higher exposure and increased risk of adverse effects, while intermediate metabolizers may experience moderate increases in drug levels. Normal metabolizers clear the drug at expected rates.

Normal Metabolizer

• Effect on drug levels: Typical clearance, standard blood concentrations.
• Clinical consequence: Expected therapeutic efficacy with standard dosing.
• Side effects: Common side effects (e.g., dizziness, somnolence) at normal frequency and severity.

Intermediate Metabolizer

• Effect on drug levels: Moderately increased blood concentrations.
• Clinical consequence: Elevated risk of adverse reactions; may require closer monitoring.
• Side effects: Moderate risk of sedation, dizziness, and cognitive effects; frequency may be higher than normal.

Poor Metabolizer

• Effect on drug levels: Significantly increased systemic exposure.
• Clinical consequence: High risk of adverse events including QT prolongation; potential for over-sedation.
• Side effects: Severe sedation, prolonged cognitive impairment; higher frequency and intensity.

Indeterminate/Not Available

• Effect: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring

CYP2C9 Dosing Guideline

No alternative treatments are specified in the FDA pharmacogenomic guideline. In clinical practice, other antiemetics—such as ondansetron or metoclopramide—may be used based on patient tolerance and response. These examples are for informational purposes only.

• FDA – Table of Pharmacogenetic Associations