Nabiximols (Sativex®): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Nabiximols is a first-in-class botanical drug substance, formulated as an oromucosal spray under the trade name Sativex®. It is a complex, standardized whole-plant extract derived from Cannabis sativa L., distinguished from herbal cannabis by its consistent composition and metered-dose delivery system. The preparation's principal active components are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), present in a precisely controlled, approximate 1:1 ratio. Its therapeutic effects are mediated through a complex modulation of the endogenous endocannabinoid system, with THC acting as a partial agonist at cannabinoid receptors (CB1 and CB2) and CBD providing synergistic and mitigating effects, including the amelioration of THC's psychoactive properties.[1]

Nabiximols has established efficacy as an adjunctive, second-line treatment for moderate-to-severe spasticity in adult patients with multiple sclerosis (MS) who have not responded adequately to other anti-spasticity medications. Clinical evidence supporting this indication is primarily based on patient-reported outcomes (PROs), which consistently demonstrate improvements in the symptomatic experience of spasticity and related symptoms such as pain and sleep disturbance. However, recent clinical trials have failed to show a statistically significant benefit on clinician-assessed, objective measures of muscle tone, such as the Modified Ashworth Scale, creating a complex evidentiary picture and posing a significant challenge for regulatory approval in jurisdictions like the United States.[4]

In select countries, including Canada, Nabiximols is also approved under conditional marketing authorizations for the symptomatic relief of neuropathic pain in MS and as an adjunctive analgesic for advanced cancer pain. Clinical trial results for these pain indications have been mixed, with some studies showing a modest but statistically significant benefit, while others have failed to meet primary endpoints, often confounded by high placebo response rates and a complex, non-linear dose-response relationship.[6]

The safety and tolerability profile of Nabiximols is well-characterized. The most common adverse events are related to the central nervous system (CNS), including dizziness, fatigue, and somnolence, which are typically mild to moderate and most prominent during the initial dose-titration period. A significant risk of serious psychiatric adverse events, including psychosis and suicidal ideation, exists, particularly at high doses. This risk necessitates careful patient selection, with an absolute contraindication for individuals with a personal or family history of psychotic illness, and requires diligent monitoring.[9]

Globally, the regulatory status of Nabiximols is fragmented. It is approved in approximately 30 countries, including the United Kingdom, Canada, and numerous European Union member states. However, as of early 2023, it remains unapproved by the United States Food and Drug Administration (FDA), with its development pathway significantly impacted by the failure of a key Phase 3 trial to meet its primary objective endpoint.[11]

1.0 Introduction: A Botanical Drug Substance

Nabiximols represents a unique pharmaceutical entity, defined not as a single, isolated small molecule but as a complex and highly characterized botanical drug substance. It is a specific, standardized herbal preparation derived from the plant Cannabis sativa L., formulated to deliver a consistent and reproducible therapeutic effect.[1]

1.1 Chemical Profile and Identification

Nabiximols is officially identified by the Chemical Abstracts Service (CAS) Registry Number 56575-23-6 and the DrugBank accession number DB14011.[1] As a combination product, its chemical properties represent the sum of its principal components. The combined molecular formula is

C42​H60​O4​, corresponding to a molecular weight of 628.94 g/mol, which is the sum of one molecule of delta-9-tetrahydrocannabinol (THC, C21​H30​O2​) and one molecule of cannabidiol (CBD, C21​H30​O2​).[1]

The formal International Union of Pure and Applied Chemistry (IUPAC) name for this combination is (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol;2--5-pentylbenzene-1,3-diol, which distinctly names the THC and CBD components, respectively.[1] Other key chemical identifiers include its InChIKey, SSNHGLKFJISNTR-DYSNNVSPSA-N, and its SMILES string, which provides a machine-readable representation of the two distinct molecular structures.[1] Throughout its development and in various registries, Nabiximols has also been known by synonyms and development codes such as Sativex®, GW-1000, and SAB-378.[1]

1.2 Composition: A Standardized Extract Beyond THC and CBD

The defining characteristic of Nabiximols is its standardized composition, which sets it apart from crude or herbal cannabis preparations. It is a whole-plant extract that has been purified and formulated to contain a defined quantity of cannabinoids, most importantly an approximate 1:1 fixed ratio of THC to CBD.[1] This consistency is achieved through a meticulous manufacturing process that begins with two distinct, specially bred chemotypes of

Cannabis sativa: one genetically selected to be high in THC and the other high in CBD.[21]

The final product is administered via a metered-dose oromucosal spray, with each 100 microliter actuation delivering a precise dose: 2.7 mg of THC and 2.5 mg of CBD.[3] This standardization of dose and formulation is fundamental to its classification as a pharmaceutical product.

Critically, the purification process is only partial, meaning the extract contains more than just its two principal cannabinoids. It also includes a consistent profile of other minor cannabinoids (such as cannabinol, cannabigerol, and cannabichromene), flavonoids, and non-cannabinoid components like terpenes (including caryophyllene and humulene).[1] While THC and CBD are considered the principal active components, the presence of this complex mixture of other plant-derived compounds is thought to contribute to the overall therapeutic profile and tolerability of the drug. This concept, often referred to as the "entourage effect," posits that the various components of the cannabis plant work synergistically, though the precise contribution of each minor component in Nabiximols has not been fully elucidated in clinical trials.

1.3 Physical and Pharmaceutical Properties

The two botanical drug substances (BDS) that constitute Nabiximols—the high-THC extract and the high-CBD extract—are physically described as brown, viscous, semi-solid (soft) extracts with the characteristic odor of cannabis.[24] Reflecting their highly lipophilic nature, these extracts are almost insoluble in water but demonstrate good solubility in most organic solvents.[24]

The final medicinal product, Sativex®, is a yellow/brown solution formulated for oromucosal administration. The active extracts are dissolved in a vehicle containing ethanol (approximately 50% v/v), propylene glycol, and peppermint oil, which serves as a flavoring agent.[23] The high ethanol content is a notable pharmaceutical characteristic that may be a consideration for patients who must avoid alcohol.[26] The product is packaged in a 10 mL Type I amber glass vial fitted with a metered-dose pump, designed to deliver up to 90 actuations of 100 microliters each after initial priming.[27] For stability, the product requires refrigeration at 2-8°C before being opened. Once in use, refrigeration is no longer necessary, but the vial should be stored upright and not exposed to temperatures above 25°C.[25]

Property	Description	Source(s)
Drug Name	Nabiximols	1
Brand Name	Sativex®	1
DrugBank ID	DB14011	1
CAS Number	56575-23-6	1
Type	Small Molecule (Combination); Botanical Drug Substance	1
Molecular Formula	C42​H60​O4​	1
Molecular Weight	628.94 g/mol	16
IUPAC Name	(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol;2--5-pentylbenzene-1,3-diol	1
InChIKey	SSNHGLKFJISNTR-DYSNNVSPSA-N	1
SMILES	CCCCCC1=CC(=C(C(=C1)O)[C@@H]2C=C(CC[C@H]2C(=C)C)C)O.CCCCCC1=CC(=C2[C@@H]3C=C(CC[C@H]3C(OC2=C1)(C)C)C)O	1
Formulation	Oromucosal spray solution	1
Active Components	Per 100µL spray: 2.7 mg THC and 2.5 mg CBD	3
Key Excipients	Ethanol anhydrous, propylene glycol, peppermint oil	23
Physical Appearance	Yellow/brown solution; BDS is a brown, viscous, semi-solid extract	24

2.0 Pharmacology and Mechanism of Action

The pharmacological activity of Nabiximols is rooted in its ability to modulate the endogenous endocannabinoid system (ECS), a ubiquitous signaling network that plays a critical role in maintaining homeostasis throughout the human body. The ECS is heavily involved in regulating a wide array of physiological processes, including pain perception, inflammation, immune response, mood, appetite, and motor control, making it a prime therapeutic target for conditions involving neuronal hyperexcitability and chronic pain.[2]

2.1 The Endocannabinoid System as a Therapeutic Target

Nabiximols exerts its effects by mimicking the actions of endogenous cannabinoids, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), at their primary receptors.[30] The two principal cannabinoid receptors are the Cannabinoid Receptor Type 1 (CB1) and Type 2 (CB2). CB1 receptors are among the most abundant G protein-coupled receptors in the central nervous system, with high concentrations in the basal ganglia, cerebellum, hippocampus, and cortex, areas that are critical for motor control, memory, and pain processing.[1] CB2 receptors are found predominantly in the periphery, particularly on cells of the immune system, where they mediate anti-inflammatory responses.[21] By interacting with these receptors, Nabiximols can influence neurotransmitter release and modulate synaptic plasticity, thereby dampening excessive neuronal signaling that underlies symptoms like spasticity and neuropathic pain.[2]

2.2 Pharmacodynamics of Tetrahydrocannabinol (THC) and Cannabidiol (CBD)

The distinct and complementary actions of the two main components of Nabiximols, THC and CBD, are central to its overall mechanism.

• Tetrahydrocannabinol (THC): Also known as dronabinol, THC is the primary psychoactive component of cannabis. It functions as a partial agonist at both CB1 and CB2 receptors.[2] Its engagement with CB1 receptors in the CNS is responsible for its principal therapeutic effects, which include analgesia, muscle relaxation, antiemesis, and appetite stimulation. The same interaction, however, also produces its characteristic and often dose-limiting psychoactive effects, such as euphoria, altered perception, anxiety, and impairment of short-term memory and cognitive function.[1]
• Cannabidiol (CBD): In contrast to THC, CBD is non-psychoactive and has a more complex and indirect mechanism of action. It has a very low affinity for CB1 and CB2 receptors but can influence the ECS in other ways. For instance, CBD is known to inhibit the enzyme Fatty Acid Amide Hydrolase (FAAH), which is responsible for breaking down the endogenous cannabinoid anandamide. By inhibiting FAAH, CBD can increase the levels and duration of action of anandamide in the synapse.[3] Furthermore, CBD interacts with a range of non-cannabinoid receptor systems, acting as an agonist at the transient receptor potential vanilloid 1 (TRPV1) ion channel, which is involved in pain perception.[3] The diverse pharmacological profile of CBD contributes to its broad therapeutic potential, which includes analgesic, anticonvulsant, muscle relaxant, anxiolytic, neuroprotective, antioxidant, and anti-psychotic activities.[1]

2.3 Synergistic and Modulatory Effects of the 1:1 Formulation

The combination of THC and CBD in a roughly 1:1 ratio is a deliberate formulation strategy based on the principle of pharmacological synergy and modulation.[11] This approach is not merely additive; it is designed to optimize the therapeutic benefits of THC while simultaneously mitigating its undesirable side effects. The anti-psychotic, anxiolytic, and anti-tachycardic properties of CBD are thought to directly counteract some of the dose-limiting adverse effects of THC, such as intoxication, anxiety, paranoia, and increased heart rate.[2] This interaction effectively widens the therapeutic window, allowing for a greater clinical effect to be achieved at a better-tolerated dose than would be possible with THC alone.

In the context of MS-related spasticity, the mechanism is believed to involve a complex interplay at the neuronal level. THC's partial agonism at presynaptic CB1 receptors, which are highly expressed on inhibitory GABAergic interneurons, can modulate the delicate balance between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission. This modulation is thought to result in a net increase in intracortical inhibition and a reduction in spinal reflex excitability, which manifests clinically as muscle relaxation and a decrease in spasticity.[2]

2.4 Molecular Targets and Receptor Binding Profile

The primary molecular targets for Nabiximols are the CB1 and CB2 receptors, where it functions as an agonist.[3] In vitro binding and functional assays have quantified its potency. For the CB1 receptor, Nabiximols has demonstrated an EC₅₀ (half maximal effective concentration) of 6.1 nM and a Ki (inhibition constant) of 10.0 nM. For the CB2 receptor, it shows an EC₅₀ of 27.9 nM and a Ki of 42.0 nM, indicating a higher affinity for the CB1 receptor.[3]

Beyond the primary cannabinoid receptors, the components of Nabiximols interact with several other targets. CBD is a known agonist at the TRPV1 (vanilloid) receptor, and interactions with various glycine receptor subunits have also been identified.[3] Additionally, Nabiximols exhibits inhibitory activity against the metabolic enzyme Cytochrome P450 2C9 (CYP2C9), with a reported IC₅₀ (half maximal inhibitory concentration) of 80,800 nM. While this is a relatively high concentration, it indicates a potential for pharmacokinetic drug-drug interactions.[3]

3.0 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Nabiximols is complex, characterized by its unique oromucosal delivery route, the high lipophilicity of its constituent cannabinoids, and extensive hepatic metabolism. These factors collectively influence its onset of action, duration of effect, and potential for drug interactions.

3.1 Oromucosal Administration and Bioavailability

Nabiximols is formulated as an oromucosal spray, with the intention of facilitating absorption through the rich vasculature of the buccal mucosa, thereby partially bypassing hepatic first-pass metabolism.[1] However, in practice, a significant portion of the administered dose is likely washed away by saliva and swallowed, leading to subsequent absorption from the gastrointestinal tract.[22] This dual absorption pathway contributes to its pharmacokinetic profile.

Absorption following oromucosal administration is relatively slow and highly variable between individuals.[17] Peak plasma concentrations (

Cmax​) of both THC and CBD are typically reached between 2 to 4 hours after a single dose.[17] This pharmacokinetic profile results in plasma concentrations of THC that are substantially lower and rise much more slowly compared to those achieved via inhalation of a similar dose. For instance, a single oromucosal dose of Sativex containing 10.8 mg of THC yields an average

Cmax​ of approximately 4 ng/mL, whereas an 8 mg dose of inhaled, vaporized THC can produce a Cmax​ exceeding 100 ng/mL within minutes.[24] This slower onset and blunted peak concentration are key to the improved tolerability of Nabiximols, as it avoids the intense psychoactive effects associated with the rapid plasma level spikes seen with inhaled cannabis.[17] The high degree of inter-subject variability in pharmacokinetic parameters underscores the clinical necessity of the "start low, go slow" dose titration schedule, as a standardized dose would be unsuitable for all patients.[24]

3.2 Distribution and Tissue Accumulation

Cannabinoids are exceptionally lipophilic (fat-soluble) compounds. Following absorption into the bloodstream, they are rapidly and widely distributed throughout the body, with a strong propensity to accumulate in adipose (fatty) tissue.[17] This fatty tissue acts as a deep compartment or reservoir for the drug. This extensive tissue distribution is a defining feature of cannabinoid pharmacokinetics and has profound clinical implications. The accumulation in fat is responsible for the slow release of cannabinoids back into the systemic circulation over an extended period, which in turn leads to a very long terminal elimination half-life.[1]

3.3 Hepatic Metabolism and Cytochrome P450 Pathways

THC and CBD undergo extensive metabolism, primarily in the liver, mediated by a wide range of cytochrome P450 (CYP) isoenzymes. Key enzymes involved in their biotransformation include CYP2C9, CYP2C19, CYP2D6, and, most notably, CYP3A4.[1] The involvement of these common metabolic pathways creates a high potential for drug-drug interactions. Nabiximols can be a "victim" of interactions, where its metabolism is altered by other drugs that inhibit or induce these enzymes, or a "perpetrator," where it affects the metabolism of other co-administered medications.[10]

THC is metabolized to several compounds, including the psychoactive metabolite 11-hydroxy-THC (11-OH-THC) and the non-psychoactive terminal metabolite 11-nor-9-carboxy-THC (THC-COOH).[17] The long elimination half-life of metabolites like THC-COOH makes them useful biomarkers for monitoring compliance or detecting cannabis use.[20]

3.4 Elimination and Half-Life

The elimination of cannabinoids from the plasma follows a bi-exponential pattern. There is an initial, relatively rapid distribution phase with a half-life of approximately 1 to 2 hours, as the drug moves from the blood into tissues. This is followed by a much slower terminal elimination phase, with a half-life typically in the range of 24 to 36 hours, and potentially longer for some individuals.[17] This prolonged terminal half-life is a direct consequence of the slow, rate-limiting release of the drug from its adipose tissue stores back into the circulation for metabolism and excretion.

The slow leaching of the drug from fat stores means that even after cessation of dosing, cannabinoids and their metabolites can be detected in the body for days or even weeks.[1] This pharmacokinetic property has important clinical consequences. For instance, it explains why the drug is contraindicated during breastfeeding, as the persistent presence of cannabinoids in the mother's system leads to accumulation in breast milk and prolonged exposure for the infant.[9] Conversely, it also provides a plausible explanation for the generally mild nature of withdrawal symptoms upon discontinuation; the drug effectively self-tapers as it is slowly eliminated from the body, preventing the abrupt drop in plasma levels that typically precipitates severe withdrawal syndromes.[26] Excretion of the metabolites occurs through both the feces (the primary route) and the urine.[17]

4.0 Clinical Evidence: Efficacy in Approved and Investigational Indications

The clinical development of Nabiximols has generated a substantial but complex body of evidence across several therapeutic areas. Its efficacy is most established for MS-related spasticity, with additional approvals for neuropathic and cancer pain in some regions. A critical theme emerging from the clinical trial data is a frequent discrepancy between subjective, patient-reported outcomes and objective, clinician-assessed measures.

4.1 Multiple Sclerosis-Associated Spasticity

Nabiximols is widely approved as an adjunctive treatment for adult patients with moderate-to-severe spasticity due to multiple sclerosis (MS) who have failed to respond adequately to first-line oral anti-spasticity medications.[29]

4.1.1 Analysis of Pivotal Phase III Trials and Responder-Enriched Designs

The efficacy of Nabiximols in MS spasticity has been demonstrated in several pivotal Phase III trials, which predominantly relied on a patient-reported 0-10 Numeric Rating Scale (NRS) as the primary endpoint for assessing spasticity severity.[4] A key and innovative feature of its clinical development was the use of a "responder-enriched" trial design. In this model, all participants initially receive open-label or single-blind Nabiximols for a trial period of four weeks. Only those patients who demonstrate a predefined initial response (typically a ≥20% reduction in their spasticity NRS score) are then eligible to be randomized into a double-blind phase, where they either continue on Nabiximols or are switched to placebo.[4]

This design effectively isolates a population of patients who are likely to benefit from the drug. In the pivotal trial employing this methodology, patients who continued on Nabiximols maintained their improvement, whereas those who switched to placebo experienced a return of their spasticity symptoms. A significantly greater proportion of patients in the Nabiximols group achieved a "clinically relevant response" (defined as a ≥30% reduction from their original baseline NRS score) compared to the placebo group.[4] A subsequent meta-analysis of seven randomized controlled trials (RCTs), encompassing 1,128 patients, corroborated these findings, concluding that the odds of being a responder on the spasticity NRS were significantly higher for patients treated with Nabiximols compared to placebo, with an odds ratio of 2.41.[39]

4.1.2 Patient-Reported vs. Clinician-Assessed Outcomes: Reconciling Disparate Findings

A significant and challenging aspect of the Nabiximols evidence base is the marked divergence between subjective and objective efficacy measures. While the drug has consistently demonstrated a statistically significant benefit on the patient-reported NRS, it has repeatedly failed to show a similar effect on clinician-assessed measures of muscle tone, such as the Modified Ashworth Scale (MAS).[5]

This discrepancy was brought into sharp focus by the recent Phase 3 RELEASE MSS1 trial (NCT04657666), a study specifically designed with an objective primary endpoint to support a New Drug Application in the United States. The trial failed to meet its primary endpoint, which was the change from baseline in the MAS Lower Limb Muscle Tone-6 (MAS LLMT-6) score. The results showed no statistically significant difference in the reduction of passive muscle tone between the Nabiximols and placebo groups.[5]

This outcome does not necessarily invalidate the patient-reported benefits. Instead, it suggests a more nuanced mechanism of action. Spasticity is a complex syndrome, and the burden it places on patients is not limited to muscle stiffness alone. It encompasses a constellation of related symptoms, including painful spasms, sleep disturbances, and bladder dysfunction. The consistent improvement seen in the NRS likely reflects Nabiximols' ability to ameliorate the patient's overall symptomatic experience of this "spasticity-plus syndrome," rather than simply reducing passive muscle tone as measured by the MAS.[40] This distinction has profound implications for regulatory evaluation, as it challenges traditional hierarchies of evidence that often prioritize objective measures over patient-reported outcomes, even when the latter may better reflect a clinically meaningful benefit for the patient.

4.1.3 Real-World Evidence and Long-Term Effectiveness

Data from real-world observational studies and long-term open-label extension trials largely support the findings from the RCTs regarding patient-perceived benefit. Large registries, such as an Italian study involving over 1,100 patients, have shown high rates of initial response, with 70.5% of patients achieving at least a 20% NRS improvement after one month of therapy.[4] Long-term data suggest that for patients who do respond, the therapeutic benefit can be durable over months or even years of continued treatment.[41]

These real-world studies also provide valuable insights into clinical practice. Patients in routine care tend to use lower average daily doses (around 6-7 sprays per day) compared to those in formal clinical trials (often >8 sprays per day), which is associated with a lower incidence of adverse events.[4] However, discontinuation rates are significant. In the Italian registry, nearly 40% of patients stopped treatment within six months, with the primary reasons being a perceived lack of effectiveness (26.2%) or intolerable adverse events (18.7%).[4] This highlights that while Nabiximols is an effective option for a subset of patients, it is not universally beneficial.

4.2 Neuropathic Pain

Nabiximols has been investigated for various chronic neuropathic pain conditions, with mixed results.

4.2.1 Efficacy in MS-Related Neuropathic Pain

In Canada, Nabiximols holds a Notice of Compliance with Conditions (NOC/c), a form of conditional approval, for the symptomatic relief of neuropathic pain in adults with MS.[6] The evidence in this specific population is generally positive. One placebo-controlled RCT reported that Nabiximols produced a nearly two-fold greater mean reduction in pain NRS scores compared to placebo. An open-label extension of that study demonstrated that this analgesic effect was sustained for up to two years of treatment, with no evidence of tolerance developing over time.[7]

4.2.2 Broader Applications in Chronic Neuropathic Pain: A Meta-Analysis Perspective

When evaluated for chronic neuropathic pain from various etiologies (including peripheral neuropathy), the evidence becomes less clear. A systematic review and meta-analysis of nine RCTs, including 1,289 participants, concluded that Nabiximols was statistically superior to placebo in reducing chronic neuropathic pain. However, the magnitude of this effect was small, with a standardized mean difference of -0.26, indicating a modest incremental benefit over background analgesia.[11]

The interpretation of this evidence is complicated by the fact that several large, well-conducted trials have failed to meet their primary endpoints, often due to an unexpectedly high placebo response rate, a common challenge in all chronic pain research.[7] Consequently, the overall strength of evidence for Nabiximols in non-MS neuropathic pain is generally considered to be low to moderate.[42]

4.3 Advanced Cancer Pain

Nabiximols is also conditionally approved in Canada as an adjunctive analgesic for adult patients with advanced cancer who experience moderate to severe pain despite receiving optimized strong opioid therapy.[6]

4.3.1 Adjunctive Analgesia in Opioid-Refractory Pain: A Review of Key Trials

The clinical trial evidence for Nabiximols in opioid-refractory cancer pain is conflicting. An early, influential study by Johnson et al. found that Nabiximols provided a statistically significant improvement in pain scores compared to placebo (p=0.024) and also significantly reduced the need for breakthrough opioid medication.[44]

However, a subsequent, larger Phase 3 trial involving 397 patients failed to replicate this finding. While there was a numerical trend in favor of Nabiximols for pain reduction, the difference between the active treatment and placebo groups did not reach statistical significance on the primary endpoint.[45]

4.3.2 Dose-Response Relationships and Conflicting Outcomes

A pivotal insight into the conflicting results came from a graded-dose trial conducted by Portenoy et al. This study randomized 360 patients to placebo or one of three dose ranges of Nabiximols: low (1-4 sprays/day), medium (6-10 sprays/day), or high (11-16 sprays/day).[8] The results revealed a complex, non-linear dose-response relationship. A statistically significant analgesic effect compared to placebo was observed in the low-dose and medium-dose groups, but not in the high-dose group.[8]

This finding suggests that for cancer pain, there may be a therapeutic ceiling, beyond which higher doses do not confer additional benefit and may even be less effective, possibly due to the confounding influence of dose-related adverse events. This highlights the critical importance of careful, individualized dose titration to find the optimal balance between efficacy and tolerability for each patient.

4.4 Investigational and Off-Label Applications

Beyond its primary approved indications, Nabiximols has been formally investigated or used off-label for a variety of other conditions. Clinical trials have explored its use for bladder dysfunction in MS, Tourette's syndrome, and for treating cannabis dependence, with some studies showing positive but preliminary signals.[3] A proof-of-concept trial in patients with motor neuron disease found that Nabiximols had a positive effect on spasticity symptoms with an acceptable safety profile.[49]

Despite not being approved for pediatric use, retrospective case series have documented its off-label use in hospitalized children for managing refractory symptoms such as pain, nausea, vomiting, and spasticity, particularly in oncology and palliative care settings.[50]

Study Identifier/Name	Phase	Design	Patient Population	Primary Endpoint	Key Conclusion/Significance	Source(s)
Pivotal Enriched Design Trial	III	Enriched, Randomized Withdrawal	MS patients with moderate-to-severe spasticity	Proportion of clinically relevant responders (≥30% NRS reduction)	Nabiximols was significantly superior to placebo in maintaining spasticity improvement in initial responders.	4
Meta-Analysis (Pattinson et al., 2023)	N/A	Meta-analysis of 7 RCTs	1,128 MS patients with refractory spasticity	Responder rate by spasticity NRS	Nabiximols is efficient in MS-associated spasticity (OR 2.41 vs. placebo).	39
RELEASE MSS1 (NCT04657666)	III	Randomized, Crossover	68 MS patients with spasticity	Change in Modified Ashworth Scale (MAS LLMT-6) score	Failed to meet primary endpoint. No significant difference between Nabiximols and placebo on this objective measure.	5

Study Identifier/Name	Indication	Design	Dosing	Key Efficacy Result	Conclusion	Source(s)
Meta-Analysis (Turcotte et al., 2021)	Chronic Neuropathic Pain	Meta-analysis of 9 RCTs	Varied	Statistically superior to placebo for pain reduction (Mean Difference -0.44).	Nabiximols is superior to placebo but with a small effect size.	42
Johnson et al. (2010)	Advanced Cancer Pain	Randomized, Placebo-Controlled	Self-titrated (avg. 8.75 sprays/day)	Statistically significant improvement in pain vs. placebo (p=0.024).	Nabiximols was effective as an adjunctive analgesic.	44
Portenoy et al. (2012)	Advanced Cancer Pain	Randomized, Placebo-Controlled, Graded-Dose	Low (1-4), Medium (6-10), High (11-16 sprays/day)	Significant pain reduction vs. placebo in Low and Medium dose groups only.	Efficacy demonstrated a non-linear dose-response; high doses were not superior.	8
Fallon et al. (2018)	Advanced Cancer Pain	Randomized, Placebo-Controlled	Self-titrated	Failed to meet primary endpoint. Numerical but not statistically significant benefit vs. placebo.	Nabiximols was not superior to placebo for the primary analysis.	45

5.0 Safety, Tolerability, and Risk Profile

The safety profile of Nabiximols has been extensively characterized through a robust clinical trial program and over a decade of post-marketing surveillance. While generally well-tolerated at recommended therapeutic doses, it is associated with a distinct profile of adverse events, primarily affecting the central nervous system, and carries specific contraindications and warnings that are critical for safe prescribing.

5.1 Common and Serious Adverse Events

The majority of adverse events (AEs) associated with Nabiximols are classified as mild to moderate in severity and tend to be most frequent and intense during the initial two-week dose-titration period, often resolving or diminishing as the patient establishes a stable, tolerated dose.[9]

• Common Adverse Events: The most frequently reported AEs are CNS-related. Dizziness is the most common, affecting up to 25% of patients, followed by fatigue, somnolence (drowsiness), or lethargy, reported in 8% to 12.5% of patients. Other common AEs (occurring in ≥1% to <10% of patients) include dry mouth, nausea, vertigo, blurred vision, disturbance in attention, memory impairment, dysgeusia (altered taste), and application site reactions such as stinging or discomfort.[9]
• Serious Adverse Events: The most significant safety concern associated with Nabiximols is the risk of serious psychiatric events, a risk that is dose-dependent and explicitly highlighted in product labeling, sometimes with a boxed warning.[9] These events can include transient psychosis, hallucinations, delusions, paranoid ideation, and, in rare cases, suicidal ideation. A study in healthy volunteers who were administered very high doses (18 actuations twice daily) found that 4 out of 41 participants experienced a transient toxic psychosis, which resolved upon cessation of the drug.[9] Other serious, though less common, AEs include syncope (fainting episodes) and an increased risk of falls, the latter being a complex outcome potentially related to both dizziness and the therapeutic effect of muscle relaxation in patients with underlying weakness.[9]

5.2 Psychiatric and Central Nervous System Effects

Beyond the risk of acute psychosis, Nabiximols is associated with a higher incidence of less severe psychiatric AEs compared to placebo. In clinical trials, approximately 17.6% of patients treated with Nabiximols experienced a psychiatric AE, compared to 7.8% of those on placebo. These events most commonly included disorientation, depression, euphoric mood, and dissociation.[9]

Cognitive effects, such as memory impairment and difficulty concentrating, are also recognized side effects.[23] Due to the potential for CNS depression, dizziness, and somnolence, patients must be strongly cautioned against driving, operating heavy machinery, or engaging in other hazardous activities if they experience any significant CNS impairment.[10]

5.3 Contraindications and High-Risk Populations

Safe use of Nabiximols requires careful patient screening to identify individuals for whom the risks may outweigh the potential benefits.

• Absolute Contraindications:
• Hypersensitivity: A known hypersensitivity or allergic reaction to cannabinoids or any of the product's excipients (ethanol, propylene glycol, peppermint oil) is an absolute contraindication.[25]
• Psychiatric History: The drug is strictly contraindicated in patients with a known or suspected personal history or a first-degree family history of schizophrenia or any other psychotic illness. It is also contraindicated in patients with a history of severe personality disorder or other significant psychiatric disorders (other than depression related to their underlying MS).[9]
• Breastfeeding: Nabiximols is contraindicated in women who are breastfeeding. Cannabinoids are highly lipophilic and are known to be excreted into breast milk in considerable concentrations, posing a risk of adverse developmental effects in the infant.[9]
• High-Risk Populations (Use with Caution):
• Elderly Patients: Individuals over 65 may be more susceptible to CNS adverse reactions, such as dizziness and confusion, which can increase the risk of falls and compromise personal safety.[9]
• Hepatic or Renal Impairment: While no specific dose adjustments are recommended, caution is advised. Impaired liver or kidney function could potentially reduce the clearance of THC and CBD, leading to drug accumulation and exaggerated or prolonged effects.[9]
• Serious Cardiovascular Disease: Nabiximols is not recommended for patients with serious cardiovascular conditions, such as severe angina or uncontrolled hypertension, as alterations in pulse rate and blood pressure have been observed, particularly during initial dose titration.[9]
• History of Epilepsy: Caution should be exercised when treating patients with a history of epilepsy or recurrent seizures.[9]
• Pregnancy and Childbearing Potential: Nabiximols is not recommended during pregnancy unless the potential benefit justifies the potential risk to the fetus. Women of childbearing potential must use a reliable method of contraception during therapy and for at least three months after discontinuation.[51]
• Children and Adolescents (<18 years): The drug is not recommended for use in this population due to a lack of established safety and efficacy, and negative results from a pediatric clinical trial.[9]

5.4 Warnings, Precautions, and Risk Mitigation

The potential for dependence on Nabiximols is considered to be low. In long-term use, patients have not been observed to escalate their daily dosage, and self-reported levels of "intoxication" are low. Abrupt withdrawal of the drug after chronic administration has not been associated with a consistent or severe withdrawal syndrome, although some patients may experience transient disturbances in sleep, mood, or appetite.[26]

A key risk mitigation strategy is embedded within the drug's approved indication for MS spasticity. The requirement for a mandatory four-week initial trial period, during which a patient must demonstrate a clinically significant improvement to continue therapy, serves as a "gatekeeper" function. This "pay-for-responders" model ensures that only patients who derive a clear benefit are exposed to the risks of long-term treatment, while non-responders are identified and treatment is discontinued promptly.[9]

System Organ Class	Adverse Event	Frequency	Clinical Notes/Management	Source(s)
Nervous System Disorders	Dizziness	Very Common (≥1/10)	Most frequent during initial titration. Usually mild-to-moderate. Patients should be warned about driving/operating machinery.	9
	Somnolence/Fatigue	Very Common (≥1/10)	Can be dose-limiting. Dose reduction or timing adjustment (e.g., more sprays in the evening) may help.	9
	Disturbance in attention, Memory impairment	Common (≥1/100 to <1/10)	Patients should be counseled on potential cognitive effects.	10
	Vertigo	Common (≥1/100 to <1/10)	Contributes to risk of falls, especially in the elderly.	9
Psychiatric Disorders	Disorientation, Euphoric mood, Dissociation	Common (≥1/100 to <1/10)	Usually mild and transient. Dose reduction may be required if persistent or distressing.	9
	Psychosis, Hallucinations, Delusions, Suicidal ideation	Uncommon/Rare	Serious adverse event. Requires immediate discontinuation of the drug and medical evaluation. Contraindicated in patients with a history of psychosis.	9
Gastrointestinal Disorders	Dry mouth, Nausea	Common (≥1/100 to <1/10)	Generally mild. Symptomatic management (e.g., hydration) is usually sufficient.	9
General Disorders and Administration Site Conditions	Fatigue, Asthenia (weakness)	Common (≥1/100 to <1/10)	May be difficult to distinguish from underlying MS symptoms.	9
	Application site pain/discomfort	Common (≥1/100 to <1/10)	Patients should be advised to rotate the application site within the mouth.	25
Injury, Poisoning and Procedural Complications	Fall	Common (≥1/100 to <1/10)	Multifactorial risk due to dizziness, muscle relaxation, and underlying MS disability.	10

6.0 Clinically Significant Drug-Drug Interactions

The complex metabolism of Nabiximols and its CNS-depressant effects create a significant potential for drug-drug interactions. These can be broadly categorized as pharmacokinetic interactions, which affect the concentration of Nabiximols or other drugs, and pharmacodynamic interactions, which involve additive physiological effects.

6.1 Pharmacokinetic Interactions via CYP450 Enzyme Modulation

Nabiximols' two primary components, THC and CBD, are extensively metabolized by the cytochrome P450 (CYP) enzyme system in the liver, particularly by the CYP3A4 and CYP2C19 isoenzymes.[1] This makes the drug susceptible to interactions with other medications that inhibit or induce these pathways.

• Effect of CYP Inhibitors on Nabiximols: Co-administration of Nabiximols with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin) or inhibitors of other relevant pathways like CYP2C9/2C19 (e.g., fluconazole) can significantly decrease the metabolism and clearance of THC and CBD. This leads to increased plasma concentrations and prolonged exposure, which can heighten the risk and severity of adverse reactions. If concomitant use is necessary, a downward re-titration of the Nabiximols dose may be required.[10]
• Effect of CYP Inducers on Nabiximols: Conversely, co-administration with strong inducers of CYP3A4 (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's Wort) can accelerate the metabolism of THC and CBD. This can lead to substantially lower plasma concentrations and may result in a loss of therapeutic efficacy. Concomitant use with strong inducers should generally be avoided if possible. If a CYP inducer is started or stopped, a re-titration of the Nabiximols dose will likely be necessary.[10]
• Effect of Nabiximols on Other Drugs: In vitro data suggest that Nabiximols and its components can also act as inhibitors of several CYP enzymes, including CYP1A2, CYP2B6, and CYP2C19, although the clinical significance at therapeutic doses is not fully established. This creates a theoretical risk that Nabiximols could increase the plasma levels of other drugs that are substrates for these enzymes (e.g., theophylline, warfarin, omeprazole), potentially requiring dose adjustments of the concomitant medication.[3]

6.2 Pharmacodynamic Interactions with CNS Depressants and Other Agents

Pharmacodynamic interactions, where drugs have additive or synergistic effects at the physiological level, are of major clinical importance for Nabiximols.

• Central Nervous System (CNS) Depressants: There is a well-established risk of additive CNS depressant effects when Nabiximols is combined with other substances that suppress central nervous system function. This combination can lead to enhanced sedation, somnolence, dizziness, and impairment of cognitive and motor skills. This significantly increases the risk of accidents, particularly falls. Clinically relevant interacting drug classes include:
• Alcohol: Patients should be strongly advised to avoid or minimize alcohol consumption, especially during the initial treatment and dose titration phase.[10]
• Benzodiazepines and other sedative/hypnotics: Drugs like alprazolam, diazepam, and zolpidem can have pronounced additive sedative effects.[17]
• Opioids: Co-administration with opioid analgesics can increase sedation and dizziness.[29]
• Other Muscle Relaxants: Additive muscle relaxant effects with agents like baclofen or tizanidine can increase the risk of falls.[23]
• Certain Antidepressants and Antipsychotics: Sedating antidepressants (e.g., mirtazapine) and antipsychotics (e.g., olanzapine) can also contribute to CNS depression.[17]
• Cardiovascular Agents: Due to the potential for cannabinoids to cause tachycardia, there may be an additive effect on heart rate when combined with other drugs that can cause tachycardia, such as anticholinergics (e.g., aclidinium), beta-agonists (e.g., albuterol/salbutamol), or adenosine.[17]

Interacting Drug/Class	Mechanism of Interaction	Potential Clinical Effect	Management Recommendation	Source(s)
CYP3A4 Inhibitors (e.g., Ketoconazole, Clarithromycin, Ritonavir)	Pharmacokinetic (Inhibition of Nabiximols metabolism)	Increased plasma concentrations of THC and CBD, leading to an increased risk of adverse events.	Caution is advised. A downward re-titration of the Nabiximols dose may be necessary.	10
CYP3A4 Inducers (e.g., Rifampicin, Carbamazepine, St. John's Wort)	Pharmacokinetic (Induction of Nabiximols metabolism)	Decreased plasma concentrations of THC and CBD, potentially leading to loss of efficacy.	Avoid concomitant use if possible. If necessary, an upward re-titration of the Nabiximols dose may be required.	10
Alcohol	Pharmacodynamic (Additive CNS depression)	Increased sedation, dizziness, and impairment of cognitive and motor skills. Increased risk of falls and accidents.	Patients should be strongly counseled to avoid or minimize alcohol intake, especially during treatment initiation.	10
Benzodiazepines (e.g., Alprazolam, Diazepam)	Pharmacodynamic (Additive CNS depression)	Pronounced increase in sedation, somnolence, and cognitive impairment.	Use with caution and monitor patients closely for excessive sedation. Dose reduction of one or both agents may be needed.	17
Opioids	Pharmacodynamic (Additive CNS depression)	Increased sedation and dizziness.	Monitor for additive side effects.	29
Other Muscle Relaxants (e.g., Baclofen, Tizanidine)	Pharmacodynamic (Additive muscle relaxation and sedation)	Increased risk of falls due to combined muscle weakness and dizziness.	Monitor for falls and excessive muscle weakness.	23

7.0 Regulatory Landscape and Global Approvals

The regulatory journey of Nabiximols is a reflection of the evolving global perspective on cannabis-based medicines. Its approval status is notably fragmented, with acceptance in many countries but significant hurdles remaining in others, most prominently the United States.

7.1 European Medicines Agency (EMA) and UK (MHRA) Approval

The United Kingdom was the first country to grant a marketing authorization for Nabiximols (marketed as Sativex®), with the Medicines and Healthcare products Regulatory Agency (MHRA) issuing its approval in June 2010.[11] Following this initial approval, Sativex® has been approved in a large number of European Union member states through mutual recognition or decentralized procedures. Countries where it holds a marketing authorization include Spain, Germany, Italy, Denmark, Sweden, Austria, the Czech Republic, and France, among others.[11]

Across the UK and the EU, the approved indication is highly specific and consistent: Sativex® is indicated as a treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.[25] This indication codifies the requirement for a four-week therapeutic trial to identify responders before committing to long-term treatment.

7.2 Health Canada Notice of Compliance with Conditions (NOC/c)

In Canada, the regulatory status of Sativex® is multifaceted. It has received a full Notice of Compliance (NOC), equivalent to a full approval, for the MS spasticity indication, consistent with its approval in Europe.[1]

In addition, Health Canada has granted a Notice of Compliance with Conditions (NOC/c) for two distinct pain indications. The NOC/c policy is designed to provide earlier market access for promising drugs intended for serious, life-threatening, or severely debilitating conditions for which there is no available alternative or the new drug represents a significant improvement. The conditional approvals for Sativex® are:

1. As an adjunctive treatment for the symptomatic relief of neuropathic pain in adult patients with multiple sclerosis.
2. As an adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain.[1]

This NOC/c status is contingent upon the manufacturer conducting further clinical trials to verify and confirm the drug's clinical benefit for these pain indications. Once this confirmatory evidence is provided and deemed satisfactory by Health Canada, the conditions on the market authorization can be removed.[29]

7.3 United States Food and Drug Administration (FDA) Status and Clinical Development Program

As of early 2023, Nabiximols is not approved by the US FDA for any indication.[11] The FDA's stance on cannabis-based products has been cautious and stringent; the agency has not approved the

Cannabis plant itself for any medical use. It has, however, approved specific, well-characterized cannabis-derived or synthetic cannabinoid drugs, such as Epidiolex (a purified CBD product) and Marinol/Syndros (synthetic dronabinol/THC).[12]

The manufacturer, Jazz Pharmaceuticals, has been pursuing a US approval pathway for Nabiximols in MS spasticity through a dedicated clinical development program. This program included a series of Phase 3 trials, designated RELEASE MSS1, MSS3, and MSS5.[11] However, this pathway encountered a major setback in mid-2022 when the company announced that the top-line results from the RELEASE MSS1 study were negative. The trial failed to meet its pre-specified primary endpoint, which was a change in the clinician-assessed Modified Ashworth Scale (MAS) for lower limb muscle tone.[5] This failure to demonstrate efficacy on an objective, physiological measure—despite a wealth of positive data on patient-reported outcomes from other studies—poses a significant hurdle for the drug's potential approval by the FDA and highlights the regulatory challenges facing symptomatic treatments that rely on subjective endpoints.

7.4 Approvals in Other Jurisdictions (e.g., Australia - TGA)

Beyond Europe and Canada, Nabiximols has gained approval in several other countries. The Therapeutic Goods Administration (TGA) in Australia approved Sativex® in November 2012 for the same MS spasticity indication as in the UK and EU.[21] It is also approved for this indication in other nations such as New Zealand, Israel, and several countries in South America.[41]

Country/Region	Regulatory Body	Approval Status	Approved Indication(s)	Key Notes	Source(s)
United Kingdom	MHRA	Approved	Adjunctive treatment for moderate-to-severe MS spasticity in adult non-responders.	First approval granted in 2010. Requires a 4-week trial period to confirm response.	38
European Union	National Agencies (via MRP/DCP)	Approved	Adjunctive treatment for moderate-to-severe MS spasticity in adult non-responders.	Approved in numerous member states (e.g., Spain, Germany, Italy).	37
Canada	Health Canada	Approved (NOC & NOC/c)	NOC: MS Spasticity. NOC/c: Neuropathic pain in MS; Advanced cancer pain.	NOC/c status is conditional, requiring further confirmatory trials for the pain indications.	6
United States	FDA	Not Approved	N/A	A Phase 3 trial (RELEASE MSS1) for MS spasticity failed to meet its primary endpoint in 2022, representing a major setback for US approval.	12
Australia	TGA	Approved	Adjunctive treatment for moderate-to-severe MS spasticity in adult non-responders.	Approved in 2012. Not listed on the Pharmaceutical Benefits Scheme (PBS).	21
New Zealand	Medsafe	Approved	Adjunctive treatment for moderate-to-severe MS spasticity in adult non-responders.	Available as a prescription medicine.	41

8.0 Synthesis and Expert Recommendations

Nabiximols occupies a unique and complex position in the modern pharmacopeia. As a standardized botanical extract, it bridges the gap between herbal cannabis and conventional single-molecule pharmaceuticals. A comprehensive evaluation of the available evidence reveals a drug with a clear, albeit niche, therapeutic role, a predictable safety profile, and a clinical development history that serves as a salient case study for the broader field of cannabinoid medicine.

8.1 A Critical Synthesis of the Evidence: Efficacy, Safety, and Place in Therapy

The totality of evidence strongly supports the use of Nabiximols as an effective second-line, adjunctive therapy for a specific subset of patients: adults with moderate-to-severe MS-related spasticity who have failed to gain adequate relief from standard oral anti-spasticity agents. Its efficacy in this population is primarily defined by a clinically meaningful improvement in the patient's subjective experience of their symptoms, as consistently demonstrated in trials using patient-reported outcome measures like the NRS. The drug appears to treat the broader "spasticity-plus syndrome," alleviating not just stiffness but also associated pain, spasms, and sleep disruption, which collectively contribute to a patient's quality of life.

The role of Nabiximols in the management of chronic pain is less well-defined. For neuropathic pain, particularly in the context of MS, the evidence suggests a modest but statistically significant benefit. For opioid-refractory advanced cancer pain, the clinical trial results are mixed and point towards a complex, non-linear dose-response curve, where low-to-medium doses appear more effective than high doses. In these pain indications, Nabiximols may be a useful option for select individuals, but it is not a universally effective analgesic, and its effect size appears to be small.

The safety profile is well-characterized and manageable for appropriately selected and monitored patients. The risk-benefit calculation is dominated by CNS-related adverse events. The common side effects of dizziness and fatigue are often transient and can be managed with slow dose titration. The more serious risk of psychiatric events, while rare, is significant and rightly forms the basis of the absolute contraindication in patients with a personal or family history of psychosis. This contraindication is the most critical element of safe prescribing.

8.2 Challenges in Clinical Trial Design for Cannabinoid-Based Medicines

The clinical development and regulatory history of Nabiximols illuminates several systemic challenges inherent in the study of cannabinoid-based medicines for symptom-based conditions.

First, the psychoactive properties of THC make true, effective blinding of clinical trials exceptionally difficult. Participants can often discern whether they are receiving the active drug or placebo, which can introduce significant bias and inflate both treatment and placebo response rates. This is a particularly vexing problem in chronic pain trials, where the placebo effect is already notoriously high.

Second, the Nabiximols story forces a critical debate on the hierarchy of clinical trial endpoints. The failure of the RELEASE MSS1 trial, which used an objective, clinician-assessed measure (MAS), stands in stark contrast to the consistent success of trials using a subjective, patient-reported measure (NRS). This raises a fundamental question for regulators and clinicians: if a drug demonstrably improves a patient's reported symptoms, function, and quality of life, should it be considered a failure because it does not alter an objective physiological parameter that may not fully capture the patient's experience of their illness? The regulatory fate of Nabiximols in the US, and potentially other cannabinoid drugs to follow, may hinge on the answer to this question and the willingness of regulatory bodies to adapt endpoint requirements for symptomatic treatments.

8.3 Future Research Directions and Unanswered Questions

While much is known about Nabiximols, several key questions remain. Future research should prioritize the identification of responder profiles. Developing clinical or biomarker-based tools to predict which patients with MS spasticity or chronic pain are most likely to benefit would allow for more targeted therapy, improving efficacy rates and avoiding unnecessary treatment trials in likely non-responders.

Further investigation into the "spasticity-plus syndrome" is warranted. Clinical trials employing composite primary endpoints that capture improvements across a range of related symptoms—such as pain, sleep quality, bladder function, and quality of life—in addition to spasticity itself, would provide a more holistic assessment of the drug's true clinical value. Finally, while short-term safety is well-understood, more prospective, long-term data on the potential for subtle cognitive or psychiatric effects with chronic, multi-year use of Nabiximols would be valuable.

8.4 Recommendations for Clinical Practice and Patient Management

Based on the available evidence, the following recommendations can be made for the clinical use of Nabiximols:

1. Patient Selection is Paramount: Prescribers should strictly adhere to the approved indication, reserving Nabiximols for patients with moderate-to-severe MS spasticity who have had an inadequate response to other anti-spasticity medications. A thorough psychiatric history must be taken to exclude any patient with a personal or family history of psychosis. Use with caution in the elderly and those with significant cardiovascular disease or a history of epilepsy.
2. Adherence to the 4-Week Trial: The mandatory four-week initial therapeutic trial is a critical component of responsible prescribing. A clinically significant improvement (e.g., ≥20% reduction in spasticity NRS) must be documented to justify continuation. If such a benefit is not observed, treatment should be discontinued to avoid exposing non-responders to long-term risks without benefit.
3. Emphasize the Titration Process: Patient education is essential for success. Clinicians must thoroughly explain the "start low, go slow" titration schedule, the rationale behind it, and the expectation that it may take up to two weeks to find an optimal dose. Patients should be counseled that side effects like dizziness are common during this period and are often manageable.
4. Counsel on Safety and Interactions: All patients must be counseled on the potential for CNS impairment and warned against driving or operating machinery until they have established a stable dose and are aware of how the medication affects them. The significant additive effects with alcohol and other CNS depressants must be explicitly discussed. Women of childbearing potential must be advised of the need for effective contraception.

Works cited

1. Nabiximols | C42H60O4 | CID 9852188 - PubChem, accessed September 9, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Nabiximols
2. Sativex in the Management of Multiple Sclerosis-Related Spasticity ..., accessed September 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4325203/
3. NABIXIMOLS - Inxight Drugs, accessed September 9, 2025, https://drugs.ncats.io/drug/K4H93P747O
4. Efficacy and safety of cannabinoid oromucosal spray for multiple ..., accessed September 9, 2025, https://jnnp.bmj.com/content/87/9/944
5. A randomized, double-blind, placebo-controlled trial to evaluate the effect of nabiximols oromucosal spray on clinical measures of spasticity in patients with multiple sclerosis - PubMed, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/39106541/
6. [115] Cannabinoids for Chronic Pain - Therapeutics Initiative, accessed September 9, 2025, https://www.ti.ubc.ca/2018/11/22/115-cannabinoids-for-chronic-pain/
7. A Review of Scientific Evidence for THC: CBD Oromucosal Spray ..., accessed September 9, 2025, https://www.tandfonline.com/doi/full/10.2147/JPR.S240011
8. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial - PubMed, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/22483680/
9. sativex (nabiximols) pump actuated metered dose aerosol 1 name of the medicine - Jazz Pharmaceuticals, accessed September 9, 2025, https://pp.jazzpharma.com/pi/sativex.au.PI.pdf
10. Nabiximols for multiple sclerosis - PMC, accessed September 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6299167/
11. Nabiximols - An alternative to Gabapentin for Neuropathic Pain - International Journal of Clinical Studies & Medical Case Reports, accessed September 9, 2025, https://ijclinmedcasereports.com/pdf/IJCMCR-CR-00578.pdf
12. FDA and Cannabis: Research and Drug Approval Process | FDA, accessed September 9, 2025, https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process
13. Sativex Does Not Meet Primary Endpoint on Measures of Spasticity for Multiple Sclerosis, accessed September 9, 2025, https://www.pharmacytimes.com/view/sativex-does-not-meet-primary-endpoint-on-measures-of-spasticity-for-multiple-sclerosis
14. Compilation of terms and definitions for Cannabis-derived ... - EMA, accessed September 9, 2025, https://www.ema.europa.eu/en/documents/other/compilation-terms-and-definitions-cannabis-derived-medicinal-products_en.pdf
15. VISDB 2.0 - UTHealth Houston, accessed September 9, 2025, https://bioinfo.uth.edu/VISDB/gene_details.php?gene=FAAH&drug_page=8
16. Nabiximols | CAS# 56575-23-6 | THC/CBD Combination - MedKoo Biosciences, accessed September 9, 2025, https://www.medkoo.com/products/30301
17. Nabiximols: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 9, 2025, https://go.drugbank.com/drugs/DB14011
18. Compound: NABIXIMOLS (CHEMBL3833333) - ChEMBL - EMBL-EBI, accessed September 9, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL3833333
19. Nabiximols | C42H60O4 | CID 9852188 - PubChem, accessed September 9, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Cannabinoids
20. Correlation of Nabiximols Dose to Steady-State Concentrations of Cannabinoids in Urine Samples from Patients with Multiple Sclerosis - MDPI, accessed September 9, 2025, https://www.mdpi.com/2077-0383/11/13/3717
21. Australian public assessment report for Nabiximols - Therapeutic Goods Administration (TGA), accessed September 9, 2025, https://www.tga.gov.au/sites/default/files/auspar-nabiximols-130927.pdf
22. Nabiximols - Wikipedia, accessed September 9, 2025, https://en.wikipedia.org/wiki/Nabiximols
23. 1.1 Nabiximols | Therapeutic Goods Administration (TGA), accessed September 9, 2025, https://www.tga.gov.au/resources/publication/scheduling-decisions-interim/publication-interim-decisions-amending-or-not-amending-current-poisons-standard-february-2019/11-nabiximols
24. AusPAR Attachment 1: Product information for Sativex (Nabiximols), accessed September 9, 2025, https://www.tga.gov.au/sites/default/files/auspar-nabiximols-130927-pi.pdf
25. Sativex Oromucosal Spray - Summary of Product Characteristics ..., accessed September 9, 2025, https://www.medicines.org.uk/emc/product/602/smpc
26. Public Assessment Report Decentralised Procedure - Geneesmiddeleninformatiebank, accessed September 9, 2025, https://www.geneesmiddeleninformatiebank.nl/pars/h111277.pdf
27. Sativex® (Nabiximols) - MS Australia, accessed September 9, 2025, https://www.msaustralia.org.au/treatment/sativex/
28. Sativex® Oromucosal Spray: Clinical and Reimbursement Information - HSE, accessed September 9, 2025, https://www.hse.ie/eng/about/who/cspd/medicines-management/managed-access-protocols/thc-cbd-sativex/sativex-clinical-reimbursement-information-document.pdf
29. SATIVEX, accessed September 9, 2025, https://pdf.hres.ca/dpd_pm/00016162.PDF
30. Analysis in relation to the newly described 'spasticity‐plus syndrome', accessed September 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9539865/
31. Pharmacokinetic evaluation of nabiximols for the treatment of multiple sclerosis pain, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/23621668/
32. A Review of Scientific Evidence for THC:CBD Oromucosal Spray (Nabiximols) in the Management of Chronic Pain - ResearchGate, accessed September 9, 2025, https://www.researchgate.net/publication/339567448_A_Review_of_Scientific_Evidence_for_THCCBD_Oromucosal_Spray_Nabiximols_in_the_Management_of_Chronic_Pain
33. pmc.ncbi.nlm.nih.gov, accessed September 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9539865/#:~:text=Nabiximols'%20mechanism%20of%20action%20involves,CB2%20receptors%20%5B13%5D.
34. Effects of sub-chronic nabiximols on biological markers of individuals undergoing a clinical trial for the treatment of cannabis use disorder - PMC - PubMed Central, accessed September 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10492088/
35. CB-13 - Inxight Drugs, accessed September 9, 2025, https://drugs.ncats.io/substance/9XRJ6055XT
36. Sativex (nabiximols) - MS Trust, accessed September 9, 2025, https://mstrust.org.uk/a-z/sativex-nabiximols
37. Sativex recommended for approval in six European countries - Almirall, accessed September 9, 2025, https://www.almirall.com/documents/portlet_file_entry/4257831/1475_EN_Sativex_MRP_day_90_press_release.pdf/fea58239-6d95-464d-8d9e-13fc0158586d
38. DMC0082 - Evidence on Drugs policy: medicinal cannabis - UK Parliament Committees, accessed September 9, 2025, https://committees.parliament.uk/writtenevidence/99484/html/
39. Nabiximols is Efficient as Add-On Treatment for Patients with Multiple Sclerosis Spasticity Refractory to Standard Treatment: A Systematic Review and Meta-Analysis of Randomised Clinical Trials - PubMed, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/37519000/
40. Effect of nabiximols oromucosal spray (Sativex®) on symptoms associated with multiple sclerosis-related spasticity: a case series - PMC - PubMed Central, accessed September 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10881112/
41. Full article: Evidence-based Management of Multiple Sclerosis Spasticity With Nabiximols Oromucosal Spray in Clinical Practice: A 10-year Recap - Taylor & Francis Online, accessed September 9, 2025, https://www.tandfonline.com/doi/full/10.2217/nmt-2022-0002
42. Nabiximols in Chronic Neuropathic Pain: A Meta-Analysis of Randomized Placebo-Controlled Trials - PubMed, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/33561282/
43. Medical Cannabis for Non-Cancer Pain: A ... - Minnesota.gov, accessed September 9, 2025, https://mn.gov/ocm/assets/medicalcannabisreport_tcm1202-628461.pdf
44. A selective review of medical cannabis in cancer pain management ..., accessed September 9, 2025, https://apm.amegroups.org/article/view/16199/html
45. A trial of Sativex for cancer related pain (GWCA0958), accessed September 9, 2025, https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-sativex-for-cancer-related-pain
46. Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain - PubMed, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/28923526/
47. Nabiximols: A New Way to Help Manage Cancer Pain, accessed September 9, 2025, https://cdn.mdedge.com/files/s3fs-public/Document/September-2017/029080002e.pdf
48. Is There a Place for Off-Label Pharmacotherapy in Cannabis Use Disorder? A Review on Efficacy and Safety - PubMed, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/26088109/
49. Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial - PubMed, accessed September 9, 2025, https://pubmed.ncbi.nlm.nih.gov/30554828/
50. Characterizing the Use of Nabiximols (Δ9-Tetrahydrocannabinol–Cannabidiol) Buccal Spray in Pediatric Patients - PMC, accessed September 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10284286/
51. Sativex® (nabiximols) (NEW) | Multiple Sclerosis Society of NZ, accessed September 9, 2025, https://msnz.org.nz/sativex-nabiximols/
52. SATIVEX® - Medsafe, accessed September 9, 2025, https://www.medsafe.govt.nz/consumers/cmi/s/sativex.pdf
53. Public Assessment Report for paediatric studies submitted in accordance with Article 46 of Regulation (EC) No1901/2006, as amen, accessed September 9, 2025, https://sukl.gov.cz/wp-content/uploads/2025/02/DELTA-9-TETRAHYDROCANNABINOL-AND-CANNABIDIOL-PAR-46-1.pdf
54. Sativex® for moderate to severe spasticity in multiple sclerosis (MS)- prescribing guideline in primary care - Derbyshire Medicines Management, accessed September 9, 2025, https://www.derbyshiremedicinesmanagement.nhs.uk/assets/Clinical_Guidelines/Formulary_by_BNF_chapter_prescribing_guidelines/BNF_chapter_4/Sativex_for_spasticity_in_MS.pdf
55. go.drugbank.com, accessed September 9, 2025, https://go.drugbank.com/drugs/DB14011#:~:text=The%20risk%20or%20severity%20of,Nabiximols%20is%20combined%20with%20Alprazolam.&text=The%20risk%20or%20severity%20of,Nabiximols%20is%20combined%20with%20Alprenolol.
56. Current legislation on medical cannabis in the European Union: historical background, movements, trends, and counter-trends lessons for Brazil - SciELO, accessed September 9, 2025, https://www.scielo.br/j/brjp/a/h58wmKqMxZWsMyJZBJTLSNS/
57. dronabinol/cannabidiol:List of nationally authorised medicinal products - PSUSA/00010844/202304, accessed September 9, 2025, https://www.ema.europa.eu/en/documents/psusa/dronabinol-cannabidiol-list-nationally-authorised-medicinal-products-psusa-00010844-202304_en.pdf