Nabilone

Nabilone is an orally active synthetic cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (CNS). It has been suggested that the antiemetic effect of nabilone is caused by interaction with the cannabinoid receptor system, i.e., the CB (1) receptor, which has been discovered in neural tissues.

Nontherapeutic Effects

Nabilone, a synthetic cannabinoid, has the potential to be abused and to produce psychological dependence. Nabilone has complex effects on the central nervous system. Its effects on the mental state (i.e., “inner mental life”) are similar to those of cannabis. Subjects given nabilone may experience changes in mood (euphoria, detachment, depression, anxiety, panic, paranoia), decrements in cognitive performance and memory, a decreased ability to control drives and impulses, and alterations in the experience of reality (e.g., distortions in the perception of objects and the sense of time, hallucinations). These phenomena appear to be more common when larger doses of nabilone are administered; however, a full-blown picture of psychosis (psychotic organic brain syndrome) may occur in patients receiving doses within the lower portion of the therapeutic range.

Data on the chronic use of nabilone are not available; experience with cannabis suggests that chronic use of cannabinoids may be associated with a variety of untoward effects on motivation, cognition, judgment, as well as other mental status changes. Whether these phenomena reflect the underlying character of individuals chronically abusing cannabis or are a result of the use of cannabis is not known.

The simultaneous use of nabilone and alcohol or barbiturates may produce additive depressive effects on central nervous system function. Possible changes in mood and other adverse behavioral effects may occur in patients receiving nabilone. Patients should remain under supervision of a responsible adult while using nabilone.

Nabilone has central nervous system activity. It produces relaxation, drowsiness, and euphoria in the recommended dosage range. Tolerance to these effects develops rapidly and is readily reversible.

In addition to effects on the mental state, nabilone has several systemic actions; most prominent are dry mouth and hypotension. Nabilone has been observed to elevate supine and standing heart rates and to cause supine and orthostatic hypotension. In clinical studies, oral administration of 2 mg of nabilone did produce some decrease in airway resistance in normal controls but had no effect in patients with asthma. No other nontherapeutic effects of clinical significance due to nabilone have been reported.

Absorption and Distribution

Nabilone appears to be completely absorbed from the human gastrointestinal tract when administered orally. Following oral administration of a 2 mg dose of radiolabeled nabilone, peak plasma concentrations of approximately 2 ng/mL nabilone and 10 ng equivalents/mL total radioactivity are achieved within 2.0 hours. The plasma half-life (T_1/2) values for nabilone and total radioactivity of identified and unidentified metabolites are about 2 and 35 hours, respectively. The initial rapid disappearance of radioactivity represents uptake and distribution of nabilone into tissue and the slower phase elimination by metabolism and excretion. The apparent volume of distribution of nabilone is about 12.5 L/kg.

Nabilone exhibits dose linearity within its therapeutic range. Clinical data suggests that the intake of food does not significantly affect either the rate or extent of absorption.

Metabolism

Metabolism of nabilone is extensive and several metabolites have been identified. Precise information concerning the metabolites that may accumulate is not available. The relative activities of the metabolites and the parent drug have not been established. There are at least two metabolic pathways involved in the biotransformation of nabilone. A minor pathway is initiated by the stereospecific enzymatic reduction of the 9-keto moiety of nabilone to produce the isomeric carbinol metabolite. The peak concentrations of nabilone and its carbinol metabolites are comparable, but their combined exposures in plasma do not account for more than 20% of that of total radioactivity. Secondly, a metabolite of nabilone in feces has been identified as a diol formed by reduction of the 9-keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain. In addition, there is evidence of extensive metabolism of nabilone by multiple P450 enzyme isoforms. In vitro P450 inhibition studies using human liver microsomes showed that nabilone did not significantly inhibit CYP1A2, 2A6, 2C19, 2D6, and 3A4 (using midazolam and nifedipine as substrates). Nabilone had a weak inhibitory effect on CYP 2E1 and 3A4 (testosterone IC₅₀ >50 µM) and had a moderate inhibitory effect on CYP2C8 and 2C9 (IC₅₀ >10 µM). However, in clinical use, the very low nabilone plasma concentration is unlikely to interfere with the P450-mediated degradation of co-administered drugs. Chronic oral administration of 1 mg t.i.d. for 14 days to 3 subjects gave no indication there was any significant accumulation of nabilone. Available evidence suggests that one or more of the metabolites has a terminal elimination half-life that exceeds that of nabilone. Consequently, in repeated use, the metabolites may accumulate at concentrations in excess of the parent drug.

Elimination

The route and rate of the elimination of nabilone and its metabolites are similar to those observed with other cannabinoids, including delta-9-THC (dronabinol). When nabilone is administered intravenously, the drug and its metabolites are eliminated mainly in the feces (approximately 67%) and to a lesser extent in the urine (approximately 22%) within 7 days. Of the 67% recovered from the feces, 5% corresponded to the parent compound and 16% to its carbinol metabolite. Following oral administration about 60% of nabilone and its metabolites were recovered in the feces and about 24% in urine. Therefore, it appears that the major excretory pathway is the biliary system.

The effects of age, gender, hepatic dysfunction, and renal insufficiency on the metabolism and elimination of nabilone have not been determined.

Special Populations

The pharmacokinetic profile of nabilone has not been investigated in either pediatric or geriatric patients.