Nabilone (DB00486): A Comprehensive Pharmacological and Clinical Monograph

1.0 Executive Summary

Nabilone is an orally active, synthetic cannabinoid and a structural analog of delta-9-tetrahydrocannabinol (Δ⁹-THC), the principal psychoactive constituent of cannabis. Identified by DrugBank ID DB00486 and CAS Number 51022-71-0, Nabilone functions as a partial agonist at both cannabinoid type 1 (CB1) and type 2 (CB2) receptors within the body's endocannabinoid system. Its therapeutic effects, particularly its antiemetic properties, are primarily mediated through its action on CB1 receptors in the central nervous system.

The United States Food and Drug Administration (FDA) has approved Nabilone for a narrow indication: the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic therapies. This positions Nabilone as a second-line or salvage agent in oncology support. Despite this limited approval, the drug is subject to extensive off-label use and investigation for a range of intractable conditions, including chronic non-cancer pain, fibromyalgia, spasticity-related pain in neurological disorders, and the suppression of nightmares associated with post-traumatic stress disorder (PTSD).

The clinical utility of Nabilone is fundamentally defined by a delicate balance between its potential therapeutic benefits and a prominent profile of adverse effects. Its safety and tolerability are dominated by dose-limiting central nervous system effects, including drowsiness, vertigo, euphoria, and potential psychiatric disturbances such as hallucinations and psychosis, which can persist for up to 72 hours after administration. Due to its psychoactive properties and potential for psychological dependence, Nabilone is classified as a Schedule II controlled substance in the United States and Canada, necessitating stringent prescribing and monitoring protocols.

Comparatively, Nabilone is more potent than dronabinol (synthetic THC) and possesses a distinct pharmacokinetic profile characterized by a longer duration of action. Its development history is unique, having been initially approved in 1985, withdrawn from the US market, and subsequently re-launched in 2006, reflecting a renewed interest in cannabinoid-based therapeutics. Current research continues to explore its potential in novel areas, such as managing agitation in Alzheimer's disease and aggression in developmental disabilities, underscoring its evolution from a niche antiemetic to a broad investigational tool for CNS disorders.

2.0 Drug Identification and Physicochemical Properties

The precise identification of a pharmaceutical agent is foundational to its study and clinical use. Nabilone is a well-characterized small molecule with a comprehensive set of identifiers across various chemical, pharmacological, and regulatory databases.

2.1 Systematic Identifiers and Nomenclature

Nabilone is known by several names and codes that facilitate its tracking in scientific literature and clinical practice. The primary brand name for Nabilone in the United States, Canada, the United Kingdom, and Mexico is Cesamet.[1] In Canada, multiple generic versions are also available, including ACT Nabilone, APO-Nabilone, pms-Nabilone, RAN-Nabilone, and TEVA-Nabilone.[3] The brand name Canemes is used in Austria and Germany.[4]

Historically and in research contexts, it has been referred to by synonyms such as Nabilon, Nabilona, Nabilonum, and the developmental codes Cpd 109514 and LY 109514.[5] The extensive catalog of identifiers from databases like ChEMBL (CHEMBL947), the Human Metabolome Database (HMDB0014629), and KEGG (D05099) reflects a long history of scientific investigation predating its modern clinical applications.[2]

2.2 Chemical and Physical Properties

Nabilone is a dibenzopyrane-derived synthetic cannabinoid.[6] As a raw material, it is described as a white to off-white polymorphic crystalline powder.[9] Its chemical structure is similar to that of Δ⁹-THC but is synthetically distinct.[2] The key physicochemical properties are summarized in Table 1. Its poor aqueous solubility (less than 0.5 mg/L across a pH range of 1.2 to 7.0) is a critical factor influencing its oral formulation and absorption characteristics.[10]

Table 1: Key Identifiers and Physicochemical Properties of Nabilone

Property	Value	Source(s)
DrugBank ID	DB00486	1
CAS Number	51022-71-0	2
Chemical Formula	C24​H36​O3​	1
Molecular Weight	372.54 g/mol	8
US Brand Name	Cesamet	1
DEA Code Number	7379	2
UNII	2N4O9L084N	2
Melting Point	159.0 °C	8
Boiling Point	457.4 °C	8
Solubility (Aqueous)	< 0.5 mg/L (pH 1.2-7.0)	10
Storage	2°C - 8°C	8

3.0 Comprehensive Pharmacological Profile

Nabilone's therapeutic and adverse effects are a direct consequence of its interaction with the endogenous cannabinoid system. Its profile is characterized by high potency, complex central nervous system activity, and a pharmacokinetic profile that leads to a prolonged duration of action.

3.1 Mechanism of Action

Nabilone exerts its pharmacological effects by acting on the endocannabinoid system (ECS), a crucial neuromodulatory system involved in regulating a wide array of physiological processes, including pain perception, memory, mood, appetite, and emesis.[2] The primary mechanism of action for Nabilone is its activity as a partial agonist at both cannabinoid type 1 (CB1) and type 2 (CB2) receptors, which are G protein-coupled receptors.[5]

• CB1 Receptors: These receptors are among the most abundant G protein-coupled receptors in the brain and are densely expressed in regions critical to Nabilone's effects, such as the hippocampus (memory), amygdala (emotional regulation), and brainstem areas that control nausea and vomiting.[5] Nabilone's agonism at CB1 receptors is believed to be the primary driver of its antiemetic, analgesic, anxiolytic, and psychoactive effects.[6]
• CB2 Receptors: These receptors are located predominantly in the peripheral nervous system and on immune cells, such as those in lymphoid tissue.[2] Activation of CB2 receptors is primarily associated with the modulation of immune function and inflammation.[2] Nabilone's activity at these receptors may contribute to its potential anti-inflammatory and analgesic properties.[13]

3.2 Pharmacodynamics

Although structurally distinct from Δ⁹-THC, Nabilone mimics its pharmacological activity and is considered to be approximately twice as potent.[2]

In vitro studies have demonstrated its high binding affinity for both cannabinoid receptors, with dissociation constants (Ki​) of 2.2 nM for CB1 and 1.8 nM for CB2.[8]

A critical nuance in Nabilone's pharmacodynamics is its classification as both highly potent and a "weak partial agonist".[2] This seemingly contradictory description highlights a key pharmacological principle. Its high potency means that it can elicit a response at very low concentrations, as reflected by its low

Ki​ values. However, as a partial agonist, it does not activate the receptor to its full capacity, unlike a full agonist. This may result in a "ceiling effect," where increasing the dose beyond a certain point does not produce a greater maximal response. This property could theoretically offer a safety advantage over full agonists by limiting maximal psychoactivity, but this is counterbalanced by its high potency, which means significant CNS effects occur even at therapeutic doses.

The complex effects of Nabilone on the CNS are dose-dependent and include the modulation of neurotransmitter systems, such as serotonin and dopamine, which contributes to its therapeutic actions and its side-effect profile.[9] These effects manifest as changes in mood (e.g., euphoria, depression, anxiety), decrements in cognitive performance and memory, and alterations in perception.[9]

3.3 Pharmacokinetics

The absorption, distribution, metabolism, and excretion (ADME) profile of Nabilone is crucial for understanding its clinical use, particularly its dosing schedule and the prolonged duration of its effects. The key pharmacokinetic parameters are summarized in Table 2.

• Absorption: Following oral administration, Nabilone is well and completely absorbed from the gastrointestinal tract, with peak plasma concentrations (Tmax​) achieved within approximately 2 hours.[5] Its absorption is consistent and not significantly affected by food.[15] However, like other oral cannabinoids, it undergoes extensive first-pass metabolism in the liver, which limits its systemic bioavailability to 10-20%.[15]
• Distribution: Nabilone is highly lipophilic, enabling it to distribute widely into body tissues, including the CNS.[15] This is reflected in its large apparent volume of distribution ( Vd​) of approximately 12.5 L/kg.[5] It is also highly bound to plasma proteins (approximately 97%), which creates the potential for drug-drug interactions through displacement of other highly protein-bound agents.[15] Due to its lipophilicity, Nabilone accumulates in adipose tissue, which acts as a reservoir from which the drug is slowly redistributed back into the bloodstream, contributing to its prolonged presence in the body.[15]
• Metabolism: Nabilone is extensively metabolized in the liver, primarily by a suite of cytochrome P450 enzymes, including CYP2E1, CYP3A4, CYP2C8, and CYP2C9.[15] The major metabolic pathway is oxidation, which produces several active and inactive metabolites, including carbinols and diols.[5] The pharmacological activity of these metabolites is not fully understood, but they are known to have a much longer half-life than the parent drug and may accumulate with repeated dosing.[11] Nabilone itself is a weak to moderate inhibitor of several CYP enzymes, suggesting a potential for metabolic interactions.[11]
• Excretion: Elimination occurs primarily through the biliary system, with approximately 60-67% of a dose recovered in the feces and 22-24% in the urine.[5] The half-life of the parent Nabilone compound is relatively short, at approximately 2 hours. However, the terminal elimination half-life of its metabolites is significantly longer, estimated at 35 hours.[5]

This pronounced mismatch between the short half-life of the parent drug and the long half-life of its metabolites is of profound clinical importance. It explains why the central nervous system effects of Nabilone, both therapeutic and adverse, can persist for a variable and unpredictable period, often lasting 48 to 72 hours after the final dose.[11] This pharmacokinetic characteristic necessitates careful patient counseling regarding activities that require mental alertness and underscores the importance of supervision during initial therapy.

Table 2: Summary of Nabilone Pharmacokinetic Parameters

Parameter	Value	Clinical Implication	Source(s)
Bioavailability	Low (10-20%)	Significant first-pass metabolism limits systemic exposure from an oral dose.	15
Time to Peak (Tmax​)	~2 hours	Onset of action is not immediate.	5
Volume of Distribution (Vd​)	~12.5 L/kg	Extensive tissue distribution, including CNS penetration; accumulation in fat.	5
Protein Binding	~97%	High potential for displacement interactions with other protein-bound drugs.	15
Metabolism	Hepatic (CYP2E1, 3A4, 2C8, 2C9)	Extensive metabolism; potential for drug-drug interactions.	15
Elimination Route	Fecal (~60-67%), Renal (~22-24%)	Primarily eliminated via the biliary system.	5
Half-life (Parent Drug)	~2 hours	Parent drug is cleared from plasma relatively quickly.	5
Half-life (Metabolites)	~35 hours	Long-lasting metabolites are responsible for the prolonged clinical effects (48-72 hours).	5

4.0 Clinical Applications and Therapeutic Efficacy

Nabilone's clinical profile is characterized by a single, narrowly defined approved indication, which stands in stark contrast to a broad and expanding landscape of off-label and investigational uses. This divergence reflects the drug's powerful, pleiotropic effects on the CNS, which clinicians have sought to harness for various treatment-refractory conditions.

4.1 Approved Indication: Management of Refractory Chemotherapy-Induced Nausea and Vomiting (CINV)

The sole indication for which Nabilone has received approval from the U.S. FDA and Health Canada is the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.[2] It is explicitly designated as a second-line or salvage therapy and is not intended for first-line or as-needed (PRN) use.[3]

This indication is a legacy of its initial development in an era before the advent of modern, highly effective antiemetics such as the serotonin 5-HT3 receptor antagonists (e.g., ondansetron) and neurokinin-1 (NK1) receptor antagonists.[20] Clinical trials from that period demonstrated that Nabilone could produce a significant reduction in the severity and duration of nausea and vomiting in approximately 50% to 70% of patients with severe symptoms refractory to then-conventional therapies like prochlorperazine.[20] In contemporary practice, its use is often governed by stringent criteria, with some guidelines and insurance policies requiring documented failure of a 5-HT3 antagonist and at least two other classes of antiemetics before Nabilone can be considered.[15]

4.2 Analysis of Off-Label Uses and Investigational Research

The majority of current clinical interest in Nabilone lies outside its approved indication, focusing on its potential utility in neurology and psychiatry for conditions that often lack effective treatments. This has led to a pattern of pharmacological repositioning, where an older drug is explored for entirely new therapeutic purposes.

4.2.1 Chronic Pain Syndromes

The off-label management of chronic non-cancer pain is one of the most common uses for Nabilone.[22] Conditions treated include neuropathic pain, fibromyalgia, and musculoskeletal pain.[1] However, the clinical evidence supporting this practice is mixed and often of low methodological quality, creating a significant gap between clinical practice and robust scientific validation.

Several retrospective chart reviews and small studies have suggested potential benefits. A review of 20 patients with chronic non-cancer pain treated with Nabilone for an average of 1.5 years found that 15 (75%) reported subjective overall improvement, with beneficial effects on sleep and nausea cited as primary reasons for continuing therapy.[26] A study in a pediatric chronic pain population found that 7 of 28 patients (25%) reported a slight improvement in pain symptoms.[25]

Conversely, systematic reviews and evidence-based guidelines have been more cautious. These analyses consistently highlight the mixed results and methodological limitations of the existing studies.[22] Consequently, recommendations from various organizations are conflicting, ranging from advising against the use of Nabilone for chronic pain to suggesting it may be considered as a third-line adjunctive therapy in select cases.[22] The uncertainty of the evidence suggests that the decision to use Nabilone for chronic pain is largely driven by clinical judgment and patient-reported outcomes in cases where conventional analgesics have failed.

4.2.2 Psychiatric Applications: PTSD and Nightmare Suppression

A growing body of evidence suggests a promising role for Nabilone in managing treatment-resistant nightmares and insomnia associated with post-traumatic stress disorder (PTSD).[29] While the evidence is still emerging and largely derived from open-label trials, retrospective studies, and surveys, the findings have been notably consistent.

An early open-label chart review of 47 patients with PTSD found that 72% experienced either complete cessation or a significant reduction in nightmares when Nabilone was added to their existing treatment regimen.[31] More recently, an anonymous online survey of 60 active Canadian Armed Forces members with PTSD who were prescribed Nabilone for chronic nightmares found that 73% of those who continued the medication reported suppression of their nightmares.[30] Many respondents also reported ancillary benefits, such as improved sleep quality, fewer night sweats, and a reduction in daytime flashbacks.[34]

A key finding from these studies is that discontinuation of Nabilone often leads to a rapid recurrence of nightmares, typically within a week, suggesting that it provides a suppressive rather than a curative effect and may be required for long-term management.[29] Despite the promising results, the American Psychiatric Association has noted the methodological weaknesses of these studies and states that more compelling data is needed before Nabilone can be recommended as a standard treatment for PTSD.[31]

4.2.3 Neurological Applications: Spasticity

Nabilone has been investigated for its potential to alleviate spasticity and spasticity-related pain in neurological conditions such as multiple sclerosis (MS) and spinal cord injury (SCI).[22] A double-blind, placebo-controlled crossover trial in patients with upper motor neuron disease found that a low dose of Nabilone (1 mg daily) significantly reduced spasticity-related pain compared to placebo, although it did not significantly alter objective measures of spasticity itself.[35] A separate pilot study involving 11 patients with SCI found that Nabilone treatment led to a significant decrease in spasticity as measured by the Ashworth Scale.[36] However, broader evidence reviews have concluded that there is currently limited or insufficient evidence to support the use of cannabinoids, including Nabilone, as an effective treatment for spasticity in most neurological conditions.[37]

4.2.4 Appetite Stimulation

While Nabilone is sometimes used off-label as an appetite stimulant for patients with cachexia or wasting disease, its efficacy for this indication is not well established.[23] There is some confusion in the literature, with a few sources suggesting it is approved for anorexia and weight loss in patients with AIDS.[2] However, the more consistent consensus is that this indication is specific to dronabinol, and Nabilone is not formally approved for appetite stimulation.[38]

4.2.5 Emerging Research: Current Clinical Trials

The continued exploration of Nabilone's therapeutic potential is evident in several ongoing or recent clinical trials targeting novel indications:

• Agitation in Alzheimer's Disease: The Nabilone for Agitation Blinded Intervention Trial (NAB-IT), identified as NCT04516057, is a randomized, double-blind, placebo-controlled study evaluating the efficacy of Nabilone in treating agitation in individuals aged 55 and older with Alzheimer's disease.[39]
• Aggression in Intellectual and Developmental Disabilities (IDD): An active Phase 1, open-label trial (NCT05273320) is currently recruiting participants to assess the safety, tolerability, and preliminary efficacy of Nabilone for managing severe behavioral problems, including aggression, in adults with IDD.[40]
• Marijuana Dependence: A completed randomized, double-blind, placebo-controlled study (NCT01025700) investigated the use of Nabilone for the outpatient management of acute marijuana withdrawal and craving, exploring its potential role in harm reduction.[41]

These trials signify a clear shift in the developmental trajectory of Nabilone, moving away from its historical role in oncology and toward its potential as a CNS-active agent for challenging neuropsychiatric and behavioral disorders.

5.0 Detailed Safety and Tolerability Profile

The clinical use of Nabilone is intrinsically limited by its safety and tolerability profile. Its potent effects on the central nervous system are responsible for both its potential therapeutic actions and its frequent, often dose-limiting, adverse effects. A thorough understanding of this profile is essential for appropriate patient selection, counseling, and monitoring.

5.1 Adverse Drug Reactions

The adverse drug reaction (ADR) profile of Nabilone is dominated by its effects on the central nervous and psychiatric systems. The incidence of side effects is high, although they are typically mild to moderate in severity and may diminish with continued use as tolerance develops.[21] The most common and significant ADRs are detailed in Table 3.

• Nervous System and Psychiatric Effects: The most frequently reported ADRs are drowsiness or somnolence (up to 66% of patients), vertigo or dizziness (up to 59%), and euphoria or a "high" feeling (up to 38%).[43] Other common effects include ataxia (unsteadiness), difficulty concentrating, and headache.[3] More severe psychiatric reactions can occur and represent a significant clinical concern. These include depression, disorientation, confusion, anxiety, panic attacks, paranoia, hallucinations, and psychosis.[11] A critical aspect of these effects is their potential to persist for 48 to 72 hours after the cessation of treatment, a consequence of the long half-life of Nabilone's active metabolites.[11]
• Cardiovascular Effects: Nabilone can cause tachycardia (fast heartbeat) and orthostatic hypotension (a drop in blood pressure upon standing), which may lead to dizziness, lightheadedness, or fainting.[3] These effects are of particular concern in elderly patients and individuals with pre-existing hypertension or heart disease.[3]
• Gastrointestinal and Anticholinergic Effects: Dry mouth is a very common side effect, reported in up to 36% of patients.[43] Nausea, anorexia, and increased appetite have also been reported.[43]
• Ocular Effects: Visual disturbances, including blurred vision, are reported in up to 13% of patients.[43]

Table 3: Comprehensive List of Adverse Drug Reactions by Frequency and System-Organ Class

System-Organ Class	Frequency	Adverse Reaction
Nervous System	Very Common (≥10%)	Drowsiness (up to 66%), Vertigo/Dizziness (up to 59%), Ataxia (up to 14%), Concentration difficulties (up to 12%)
	Common (1%-10%)	Headache, Sedation
	Frequency not reported	Syncope, Tremor, Memory disturbance, Convulsions, Paresthesia, Coordination disturbance
Psychiatric	Very Common (≥10%)	Euphoria (up to 38%), Depression (up to 14%), Sleep disturbance (up to 11%)
	Common (1%-10%)	Dysphoria, Disorientation, Depersonalization syndrome
	Frequency not reported	Hallucinations, Confusion, Anxiety, Paranoia, Psychosis, Panic disorder
Gastrointestinal	Common (1%-10%)	Dry mouth (up to 36%)
	Uncommon (0.1%-1%)	Nausea
	Frequency not reported	Vomiting, Abdominal pain, Constipation
Ocular	Very Common (≥10%)	Visual disturbance (up to 13%)
	Frequency not reported	Eye dryness, Pupil dilation, Photophobia
Cardiovascular	Common (1%-10%)	Hypotension
	Frequency not reported	Orthostatic hypotension, Tachycardia, Palpitations, Hypertension
Metabolic	Common (1%-10%)	Anorexia, Increased appetite
Other	Common (1%-10%)	Asthenia (weakness)
	Frequency not reported	Fatigue, Tinnitus, Flushing, Malaise, Irritability

Source: Compiled from data in.[43]

5.2 Clinically Significant Interactions

Nabilone has the potential for numerous clinically significant drug interactions, primarily due to its CNS depressant effects and its metabolism by the cytochrome P450 system. The most critical interactions are summarized in Table 4.

The primary concern is the additive or synergistic CNS depression when Nabilone is co-administered with other substances that slow brain activity. This includes alcohol, opioids, benzodiazepines, barbiturates, sedating antihistamines, and tricyclic antidepressants.[3] Such combinations can lead to profound sedation, respiratory depression, and impaired psychomotor function, and should generally be avoided.[11]

Table 4: Clinically Significant Drug Interactions with Nabilone

Interacting Drug/Class	Potential Effect	Clinical Management Recommendation	Source(s)
CNS Depressants (e.g., Alcohol, Opioids, Benzodiazepines, Barbiturates, Sedatives)	Additive or synergistic CNS depression, profound sedation, respiratory depression, psychomotor impairment.	Avoid combination. If co-administration is necessary, limit dosages and durations and monitor closely for sedation and respiratory depression.	3
Sympathomimetic Agents (e.g., Amphetamines, Cocaine)	Additive hypertension and tachycardia; potential increase in cardiotoxic risk.	Use with caution and monitor cardiovascular parameters.	15
Anticholinergic Agents (e.g., Atropine, Scopolamine, some Antihistamines)	Enhanced tachycardia and CNS effects, including sedation and confusion.	Use with caution and monitor for increased anticholinergic and CNS side effects.	15
Highly Protein-Bound Drugs (e.g., Warfarin, Phenytoin)	Nabilone may displace other drugs from plasma proteins, increasing their free concentration and potential toxicity.	Monitor for altered pharmacological effects or toxicity of the co-administered drug.	15
CYP450 Inducers/Inhibitors	Co-administration may alter the metabolism of Nabilone, affecting its plasma concentrations and clinical effects.	Use with caution and monitor for changes in efficacy or toxicity.	11

5.3 Contraindications, Warnings, and Precautions

The safety profile of Nabilone dictates a specific set of contraindications and warnings to mitigate the risk of serious adverse events.

• Contraindications:
• Hypersensitivity: Nabilone is contraindicated in any patient with a history of hypersensitivity to Nabilone or any other cannabinoid, including natural marijuana.[11]
• Psychiatric History: It is contraindicated in patients with a history of psychotic reactions (e.g., schizophrenia) or severe mental illness.[3]
• Warnings and Precautions:
• CNS Impairment: Patients must be strictly warned not to drive, operate heavy machinery, or engage in any potentially hazardous activity while taking Nabilone, as it significantly impairs mental and physical abilities.[11]
• Supervision: Patients should remain under the supervision of a responsible adult, especially during the initial phase of treatment and during any dose adjustments, due to the unpredictable nature of its CNS effects.[9]
• Cardiovascular Disease: Use with caution in elderly patients and in those with hypertension or heart disease due to its effects on heart rate and blood pressure.[3]
• History of Substance Abuse: Use with caution in individuals with a personal or family history of substance abuse, including alcohol or drug dependence.[3]
• Hepatic Impairment: Use with extreme caution in patients with severe liver dysfunction, as Nabilone is extensively metabolized by the liver.[44]
• Special Populations: The safety and efficacy of Nabilone have not been established in pediatric patients (<18 years), pregnant women, or nursing mothers. Its use in these populations is generally not recommended.[3]

5.4 Potential for Abuse, Dependence, and Withdrawal

As a synthetic cannabinoid with psychoactive effects similar to cannabis, Nabilone has a recognized potential for abuse and the production of psychological dependence.[2] This potential is the primary reason for its classification as a Schedule II controlled substance in the United States.[2] However, several factors may mitigate its real-world abuse liability. Research and expert opinion suggest that its abuse potential is lower than that of smoked cannabis due to its slow oral onset of action, longer time to peak effect, and a side-effect profile where unpleasant effects like drowsiness and vertigo are more prominent than the desired euphoria.[20] Population-level data and reviews of law enforcement and medical databases have found extremely rare instances of Nabilone abuse or diversion.[24] Nonetheless, prescribers must monitor patients for signs of misuse, abuse, or dependence.[11]

6.0 Regulatory Status and Prescribing Information

The prescribing and dispensing of Nabilone are strictly regulated due to its pharmacological properties and abuse potential. Its regulatory status varies internationally, reflecting different national approaches to cannabinoid-based medicines.

6.1 Controlled Substance Scheduling

The legal classification of Nabilone is a critical factor governing its availability and use.

• United States: The U.S. Drug Enforcement Administration (DEA) classifies Nabilone as a Schedule II controlled substance under the Controlled Substances Act. This schedule is for drugs with a high potential for abuse, with use potentially leading to severe psychological or physical dependence, but which also have a currently accepted medical use.[2]
• Canada: Under the Controlled Drugs and Substances Act (CDSA), Nabilone is listed in Schedule II, which includes cannabis and its derivatives.[52]
• Europe and the United Kingdom: The regulatory landscape in Europe is more fragmented. Nabilone is not centrally authorized by the European Medicines Agency (EMA).[4] Instead, it is authorized for use on a national level in several countries, including the United Kingdom, Austria, and Germany.[4] While Δ⁹-THC is strictly controlled under international conventions, Nabilone as a synthetic analogue is not, which allows individual member states to regulate it under their own national laws.[57]

This regulatory heterogeneity highlights the complex and evolving global perspective on cannabinoid therapeutics, with the U.S. and Canada applying a high level of control based on abuse potential, while European nations have adopted a more varied, country-by-country approach.

6.2 Dosage, Administration, and Patient Counseling

Proper dosing and comprehensive patient education are paramount to maximizing the efficacy and minimizing the risks of Nabilone therapy.

• Dosage for CINV: The recommended adult oral dose is 1 mg or 2 mg twice daily. To minimize side effects, therapy should be initiated at the lower dose and titrated upwards as needed. On the day of chemotherapy, the first dose should be administered 1 to 3 hours prior to the chemotherapeutic agent. A dose of 1 mg or 2 mg the night before chemotherapy may also be beneficial. The maximum recommended daily dose is 6 mg, administered as 2 mg three times a day.[3]
• Administration: Nabilone is supplied as oral capsules (0.25 mg, 0.5 mg, and 1 mg strengths) and can be taken with or without food.[16] Prescriptions should be limited to the quantity necessary for a single cycle of chemotherapy to minimize the risk of diversion or misuse.[9]
• Patient Counseling: Patients and their caregivers must be thoroughly counseled on several key points:
• CNS Impairment: Emphasize that the drug causes drowsiness, dizziness, and cognitive impairment. Patients must not drive, operate machinery, or perform any hazardous tasks while under its influence.[11]
• Prolonged Effects: Explain that these impairing effects can persist for 48 to 72 hours after the last dose.[16]
• Supervision: A responsible adult must supervise the patient during initial use and dose adjustments.[11]
• Substance Avoidance: Instruct patients to avoid alcohol and other CNS depressants, including illicit substances like marijuana, as they can cause additive effects.[3]
• Orthostatic Hypotension: Advise patients to rise slowly from a sitting or lying position to minimize the risk of dizziness and fainting.[3]
• Abuse Potential: Discuss the habit-forming potential of the medication and the importance of taking it exactly as prescribed.[16]

6.3 Commercial Formulations, Brand Names, and Manufacturers

Nabilone is marketed globally under several brand names. The originator brand is Cesamet.[1] The original developer of the compound was Eli Lilly and Company.[20] The rights were later acquired by Valeant Pharmaceuticals International, which has since been renamed Bausch Health Companies.[20] In Europe, manufacturers include AOP Orphan Pharmaceuticals GmbH (for Canemes) and Brown & Burk UK Ltd (for generic Nabilone).[4] Numerous other companies are involved in the manufacturing of the active pharmaceutical ingredient (API).[61]

7.0 Comparative Analysis and Historical Context

To fully appreciate Nabilone's position in modern medicine, it is essential to compare it with its closest therapeutic relative, dronabinol, and to understand its unique developmental history.

7.1 Nabilone versus Dronabinol

Nabilone and dronabinol are the two most commonly prescribed synthetic cannabinoids in North America. While they share a similar mechanism of action and therapeutic class, they possess key differences in chemistry, pharmacology, regulation, and clinical use that are critical for informed prescribing. A comparative summary is provided in Table 5.

• Chemical Identity: The most fundamental difference is their chemical structure. Dronabinol (marketed as Marinol® and Syndros®) is synthetic Δ⁹-THC, making it chemically identical to the primary psychoactive component of the cannabis plant. In contrast, Nabilone is a synthetic analog of THC; it is an engineered molecule designed to mimic THC's effects but is structurally distinct.[5]
• Pharmacology and Potency: Nabilone is considered to be approximately twice as potent as dronabinol.[2] Pharmacokinetically, dronabinol has a faster onset of action (approximately 30 minutes), whereas Nabilone has a significantly longer duration of action, typically lasting 8 to 12 hours and sometimes up to 24 hours.[38] Furthermore, Nabilone is metabolized into fewer metabolites than dronabinol, which some have suggested may reduce the risk of toxicity from metabolite accumulation.[14]
• Approved Indications: Both drugs are FDA-approved for refractory CINV. However, dronabinol holds an additional FDA approval for the treatment of anorexia associated with weight loss in patients with AIDS, an indication for which Nabilone is not formally approved, despite some off-label use.[23]
• Regulatory Status: In the United States, their differing perceived abuse potentials are reflected in their DEA scheduling. Nabilone is a Schedule II drug, whereas dronabinol is classified as a Schedule III substance, indicating a lower perceived potential for abuse and dependence.[38]
• Formulation and Cost: Dronabinol contains sesame oil in its capsule formulation, which poses a risk of anaphylaxis in patients with sesame or nut allergies; Nabilone does not have this issue.[38] Clinically, Nabilone is often reported to be less expensive than dronabinol.[38]

Table 5: Comparative Profile of Nabilone and Dronabinol

Feature	Nabilone (Cesamet®)	Dronabinol (Marinol®)	Source(s)
Chemical Identity	Synthetic THC analog	Synthetic THC	38
US DEA Schedule	Schedule II	Schedule III	38
FDA-Approved Indications	Refractory CINV	Refractory CINV; Anorexia in AIDS	15
Potency (vs. THC)	~2x more potent	1x (chemically identical)	2
Onset of Action	Slower	Faster (~30 mins)	38
Duration of Action	Longer (8-12+ hours)	Shorter	38
Key PK Difference	Fewer metabolites	More metabolites	14
Allergen Risk	None specified	Contains sesame oil	38
Cost	Typically less expensive	Typically more expensive	38

7.2 Developmental History

The history of Nabilone is that of a drug developed for one purpose, overshadowed by newer innovations, and later revived for a new era of medicine. Its journey began in the early 1970s at Eli Lilly and Company, spurred by anecdotal reports from young cancer patients that smoking cannabis alleviated the severe nausea and vomiting caused by chemotherapy.[20]

Nabilone received its first FDA approval in 1985 for refractory CINV.[2] However, its market presence was short-lived. This period coincided with the development and launch of the first 5-HT3 receptor antagonists, such as ondansetron, which offered superior antiemetic efficacy with a far more favorable side-effect profile. Faced with this new class of drugs, older antiemetics with significant CNS side effects, including Nabilone, became less commercially viable. Consequently, Eli Lilly withdrew Nabilone from the U.S. market in 1989, citing "commercial reasons".[20]

Despite its withdrawal from the U.S., Nabilone remained approved and in use in other countries, notably Canada, where it was first approved in 1981.[24] A renewed interest in the therapeutic potential of cannabinoids in the early 2000s set the stage for its return. In 2004, Valeant Pharmaceuticals International (now Bausch Health Companies) acquired the rights to Cesamet from Eli Lilly.[59] After securing a new marketing approval from the FDA, Valeant re-launched Nabilone in the United States in 2006.[2] This re-launch was not aimed at competing with first-line antiemetics but rather at filling the niche for refractory CINV and capitalizing on the growing exploration of cannabinoids for a wide range of off-label indications.

8.0 Synthesis and Expert Insights

Nabilone occupies a unique and complex position in contemporary pharmacotherapy. Its profile is defined by a central therapeutic dilemma: the need to balance its potential efficacy in difficult-to-treat conditions against a substantial and predictable burden of central nervous system adverse effects. Originally developed as an antiemetic, it has been largely superseded in this role by safer, more effective agents. Yet, it has found a second life as an important tool for clinicians and researchers exploring the therapeutic potential of the endocannabinoid system.

The established efficacy of Nabilone is confined to its narrow, FDA-approved indication for refractory CINV, a clinical niche that has shrunk with the advancement of modern antiemetic regimens. The true drivers of its current use are the numerous off-label applications in neurology and psychiatry, particularly for chronic neuropathic pain, fibromyalgia, and PTSD-associated nightmares. In these areas, where conventional therapies often fail, Nabilone offers a novel mechanism of action. However, the evidence supporting these uses remains largely preliminary, derived from small, often uncontrolled studies. This has created a significant evidence-practice gap, where clinical use has outpaced rigorous scientific validation.

The primary barrier to broader application and higher-dose therapy is Nabilone's safety profile. The high incidence of dose-limiting CNS effects—such as somnolence, dizziness, cognitive impairment, and potential psychiatric disturbances—necessitates careful patient selection, intensive counseling, and stringent monitoring. Its classification as a Schedule II controlled substance further underscores the regulatory concerns regarding its abuse potential, even though real-world abuse appears to be rare. The drug's pharmacokinetic properties, especially the long half-life of its active metabolites, result in a prolonged duration of action that can be both a therapeutic advantage and a safety concern, as adverse effects can persist for days after discontinuation.

Looking forward, the future of Nabilone lies in clarifying its role in these off-label and investigational domains. There is an urgent need for high-quality, long-term, randomized controlled trials to definitively establish its efficacy and safety in chronic pain, PTSD, and spasticity. The ongoing trials in Alzheimer's-related agitation and aggression in developmental disabilities represent promising steps in this direction. Further research into the pharmacology of its long-lasting metabolites could also provide a clearer understanding of its extended duration of effect and inform the development of future cannabinoid-based therapeutics with improved safety profiles.

In conclusion, Nabilone is a historically significant cannabinoid therapeutic that serves as a valuable, albeit challenging, option for a small subset of patients with refractory CINV. Its more important contemporary role may be as a pharmacological probe, providing critical insights into the function of the endocannabinoid system and paving the way for the next generation of medicines for some of the most intractable disorders of the central nervous system.

Works cited

1. Nabilone - brand name list from Drugs.com, accessed September 2, 2025, https://www.drugs.com/ingredient/nabilone.html
2. Nabilone | C24H36O3 | CID 5284592 - PubChem, accessed September 2, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Nabilone
3. Nabilone (oral route) - Side effects & dosage - Mayo Clinic, accessed September 2, 2025, https://www.mayoclinic.org/drugs-supplements/nabilone-oral-route/description/drg-20064938
4. nabilone: List of nationally authorised medicinal products - PSUSA ..., accessed September 2, 2025, https://www.ema.europa.eu/en/documents/psusa/nabilone-list-nationally-authorised-medicinal-products-psusa-00002100-202312_en.pdf
5. Nabilone: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 2, 2025, https://go.drugbank.com/drugs/DB00486
6. Definition of nabilone - NCI Drug Dictionary, accessed September 2, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/nabilone
7. nabilone - Drug Central, accessed September 2, 2025, https://drugcentral.org/drugcard/1862
8. Nabilone | 51022-71-0 | FN126318 - Biosynth, accessed September 2, 2025, https://www.biosynth.com/p/FN126318/51022-71-0-nabilone
9. Cesamet® (nabilone) Capsules DESCRIPTION CLINICAL PHARMACOLOGY - accessdata.fda.gov, accessed September 2, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/018677Orig1s017lbl.pdf
10. Cesamet® (nabilone) Capsules DESCRIPTION CLINICAL PHARMACOLOGY - BauschHealth Prescribing Information, accessed September 2, 2025, https://pi.bauschhealth.com/globalassets/BHC/PI/CESAMET-PI.pdf
11. CESAMET™ (nabilone) Capsules - accessdata.fda.gov, accessed September 2, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018677s011lbl.pdf
12. Nabilone | CAS 51022-71-0 - Veranova, accessed September 2, 2025, https://veranova.com/controlled-substances/nabilone/
13. What is the mechanism of Nabilone? - Patsnap Synapse, accessed September 2, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-nabilone
14. Pharmacokinetic overview of cannabinoids [5, 12] | Download Table - ResearchGate, accessed September 2, 2025, https://www.researchgate.net/figure/Pharmacokinetic-overview-of-cannabinoids-5-12_tbl2_6660412
15. Cannabinoid Antiemetic Therapy - StatPearls - NCBI Bookshelf, accessed September 2, 2025, https://www.ncbi.nlm.nih.gov/books/NBK535430/
16. Nabilone: MedlinePlus Drug Information, accessed September 2, 2025, https://medlineplus.gov/druginfo/meds/a607048.html
17. Nabilone - Family Health Associates, accessed September 2, 2025, https://fhahermiston.com/patient-education/healthwise/?DOCHWID=a607048
18. CP.PMN.160 Nabilone (Cesamet) - Ambetter Health, accessed September 2, 2025, https://www.ambetterhealth.com/content/dam/centene/mhsindiana/policies/pharmacy-policies/CP.PMN.160%20Nabilone.pdf
19. Nabilone Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed September 2, 2025, https://www.drugs.com/dosage/nabilone.html
20. (PDF) Nabilone (Cesamet®) Production and Use - ResearchGate, accessed September 2, 2025, https://www.researchgate.net/publication/366856076_Nabilone_CesametR_Production_and_Use
21. Nabilone. A preliminary review of its pharmacological properties and therapeutic use, accessed September 2, 2025, https://pubmed.ncbi.nlm.nih.gov/2863127/
22. Nabilone for Chronic Pain Management: A Review of Clinical Effectiveness and Guidelines – An Update - NCBI, accessed September 2, 2025, https://www.ncbi.nlm.nih.gov/books/NBK538943/
23. Nabilone - LiverTox - NCBI Bookshelf, accessed September 2, 2025, https://www.ncbi.nlm.nih.gov/books/NBK547865/
24. The abuse potential of the synthetic cannabinoid nabiloneadd_2776 494..503, accessed September 2, 2025, http://www.biblioteca.cij.gob.mx/Archivos/Materiales_de_consulta/Drogas_de_Abuso/Articulos/47922818.pdf
25. Synthetic cannabinoid for the treatment of severe chronic noncancer pain in children and adolescents - Taylor & Francis Online, accessed September 2, 2025, https://www.tandfonline.com/doi/full/10.1080/24740527.2022.2132138
26. Experience with the Synthetic Cannabinoid Nabilone in Chronic Noncancer Pain - Oxford Academic, accessed September 2, 2025, https://academic.oup.com/painmedicine/article/7/1/25/1859088
27. Nabilone for Chronic Non-Cancer Pain | CDA-AMC - Canada's Drug Agency, accessed September 2, 2025, https://www.cda-amc.ca/nabilone-chronic-non-cancer-pain
28. Nabilone for Chronic Non-Cancer Pain - Canada's Drug Agency, accessed September 2, 2025, https://www.cda-amc.ca/sites/default/files/pdf/htis/2024/RC1539-Nabilone-for-Chronic-Non-Cancer-Pain.pdf
29. Indications for nabilone (all off-label). - ResearchGate, accessed September 2, 2025, https://www.researchgate.net/figure/Indications-for-nabilone-all-off-label_fig2_263710464
30. Use of a synthetic cannabinoid (nabilone) in the ongoing management of posttraumatic stress disorder nightmares in the Canadian Armed Forces: Results of an anonymous online survey - ResearchGate, accessed September 2, 2025, https://www.researchgate.net/publication/343789478_Use_of_a_synthetic_cannabinoid_nabilone_in_the_ongoing_management_of_posttraumatic_stress_disorder_nightmares_in_the_Canadian_Armed_Forces_Results_of_an_anonymous_online_survey
31. Resource Document on APA Opposition to the Use of Cannabis for PTSD - American Psychiatric Association, accessed September 2, 2025, https://www.psychiatry.org/getattachment/817ea9d9-21fa-4fef-ba7e-950367e6f47a/Resource-Document-2019-APA-Opposition-to-the-Use-of-Cannabis-for-PTSD.pdf
32. The Use of a Synthetic Cannabinoid in the Management of Treatment‐Resistant Nightmares in Posttraumatic Stress Disorder (PTSD), accessed September 2, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6494011/
33. Use of a synthetic cannabinoid (nabilone) in the ongoing management of posttraumatic stress disorder nightmares in the Canadian, accessed September 2, 2025, https://utppublishing.com/doi/pdf/10.3138/jmvfh-2019-0028
34. Medical Cannabis for the Management of PTSD-associated Nightmares - Curaleaf Clinic, accessed September 2, 2025, https://curaleafclinic.com/medical-cannabis-for-the-management-of-ptsd-associated-nightmares/
35. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain - A double-blind placebo-controlled cross-over trial - ResearchGate, accessed September 2, 2025, https://www.researchgate.net/publication/6805237_Low_dose_treatment_with_the_synthetic_cannabinoid_Nabilone_significantly_reduces_spasticity-related_pain_-_A_double-blind_placebo-controlled_cross-over_trial
36. A Randomized, Double-Blinded, Crossover Pilot Study Assessing the Effect of Nabilone on Spasticity in Persons With Spinal Cord Injury | Request PDF - ResearchGate, accessed September 2, 2025, https://www.researchgate.net/publication/43533639_A_Randomized_Double-Blinded_Crossover_Pilot_Study_Assessing_the_Effect_of_Nabilone_on_Spasticity_in_Persons_With_Spinal_Cord_Injury
37. Guidance on the suggested use of medical cannabis Persistent and debilitating muscle spasms - Utah.gov, accessed September 2, 2025, https://medicalcannabis.utah.gov/wp-content/uploads/Persistent-and-debilitating-muscle-spasms-guidance.pdf
38. Cannabinoids in the Treatment of Symptoms in Serious Illness ..., accessed September 2, 2025, https://www.mypcnow.org/fast-fact/cannabinoids-in-the-treatment-of-symptoms-in-cancer-and-aids/?print=print
39. Nabilone for Agitation Blinded Intervention Trial | CAMH, accessed September 2, 2025, https://www.camh.ca/en/science-and-research/research-connect/nabilone-for-agitation-blinded-intervention-trial
40. Clinical Trial of Nabilone for Aggression in Adults with Intellectual ..., accessed September 2, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT05273320/clinical-trial-of-nabilone-for-aggression-in-adults-with-intellectual-and-developmental-disabilities
41. Study Details | Nabilone & Marijuana Addiction | ClinicalTrials.gov, accessed September 2, 2025, https://clinicaltrials.gov/study/NCT01025700
42. The Safety of Dronabinol and Nabilone: A Systematic Review and Meta-Analysis of Clinical Trials - ResearchGate, accessed September 2, 2025, https://www.researchgate.net/publication/357883066_The_Safety_of_Dronabinol_and_Nabilone_A_Systematic_Review_and_Meta-Analysis_of_Clinical_Trials
43. Nabilone Side Effects: Common, Severe, Long Term - Drugs.com, accessed September 2, 2025, https://www.drugs.com/sfx/nabilone-side-effects.html
44. Nabilone | Drug Lookup | Pediatric Care Online - AAP Publications, accessed September 2, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5110/Nabilone
45. Details for: CESAMET - Drug and Health Product Register, accessed September 2, 2025, https://hpr-rps.hres.ca/details.php?drugproductid=385&query=
46. Nabilone: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed September 2, 2025, https://www.rxlist.com/nabilone/generic-drug.htm
47. publications.aap.org, accessed September 2, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5110/Nabilone#:~:text=Contraindications-,Contraindications,formulation%3B%20history%20of%20psychotic%20reactions.
48. Nabilone | Memorial Sloan Kettering Cancer Center, accessed September 2, 2025, https://www.mskcc.org/cancer-care/patient-education/medications/adult/nabilone?mode=large&msk_tools_print=pdf
49. Cesamet (nabilone): Uses, Side Effects, Dosage & Reviews - GoodRx, accessed September 2, 2025, https://www.goodrx.com/cesamet/what-is
50. MID LEVEL PRACTITIONERS - Controlled Substance Authority by Discipline within State - DHHS, accessed September 2, 2025, https://dhhs.ne.gov/licensure/Open%20Meeting%20Act%20Docs/APRN%205.20.22%20C1a%20DEA%20-%20Midlevel%20Pracitioners%20by%20State.pdf
51. Drug Scheduling - DEA.gov, accessed September 2, 2025, https://www.dea.gov/drug-information/drug-scheduling
52. Controlled Drugs and Substances Act - Laws.justice.gc.ca, accessed September 2, 2025, https://laws-lois.justice.gc.ca/eng/acts/c-38.8/page-10.html
53. Classifications of Controlled Substances: Insights from 23 Countries - Publishing Services, accessed September 2, 2025, https://pubs.lib.umn.edu/index.php/innovations/article/download/383/377/552
54. National registers of authorised medicines | European Medicines Agency (EMA), accessed September 2, 2025, https://www.ema.europa.eu/en/medicines/national-registers-authorised-medicines
55. chapter 5 medical use of cannabis and cannabinoids: review of the evidence, accessed September 2, 2025, https://publications.parliament.uk/pa/ld199798/ldselect/ldsctech/151/15106.htm
56. A Regulatory Take on Cannabis and Cannabinoids for Medicinal use in the European Union, accessed September 2, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7837236/
57. European Legal Database on Drugs - euda.europa.eu, accessed September 2, 2025, https://www.euda.europa.eu/system/files/media/publications/documents/10743/Medical_cannabis_FINAL.pdf
58. Nabilone - AdisInsight - Springer, accessed September 2, 2025, https://adisinsight.springer.com/drugs/800025856
59. Valeant Pharmaceuticals International Receives FDA Marketing Approval For Cannabinoid Cesamet(TM) (CII) - BioSpace, accessed September 2, 2025, https://www.biospace.com/valeant-pharmaceuticals-international-receives-fda-marketing-approval-for-cannabinoid-cesamet-tm-cii
60. Nabilone 1mg Capsule - Summary of Product Characteristics (SmPC) - (emc) | 12767, accessed September 2, 2025, https://www.medicines.org.uk/emc/product/12767/smpc
61. Nabilone API Manufacturers | Suppliers | Drug Master Files (DMF) - PharmaCompass.com, accessed September 2, 2025, https://www.pharmacompass.com/manufacturers-suppliers-exporters/nabilone
62. Valeant returns synthetic cannabinoid to USA - PharmaTimes, accessed September 2, 2025, https://pharmatimes.com/news/valeant_returns_synthetic_cannabinoid_to_usa_996830/