The Green Revolution in Multiple Sclerosis Therapy
For the millions living with multiple sclerosis (MS), spasticity—painful muscle stiffness and spasms—represents one of the most debilitating aspects of their disease. Conventional treatments often provide insufficient relief, leaving patients searching for alternatives. Enter nabiximols (Sativex®), a cannabis-based oromucosal spray containing balanced amounts of tetrahydrocannabinol (THC) and cannabidiol (CBD), which has emerged as an effective add-on therapy for MS spasticity. But why do approximately 30-40% of patients not respond to this treatment? The answer lies deep within our genes, where complex networks and biological pathways determine our individual response to therapy 1 2 .
Recent breakthroughs have begun to unravel the intricate relationship between nabiximols and our genetic blueprint. Scientists are now discovering that the drug's effectiveness extends far beyond simple symptom relief, modulating entire immune pathways and being influenced by specific genetic variations. This personalized dimension to treatment response represents a paradigm shift in how we approach MS therapy, moving us closer to an era where genetic testing could predict which patients will benefit most from this cannabis-based treatment 3 .
Specific gene variants influence treatment response
Nabiximols calms overactive immune pathways
Future treatments tailored to individual genetics
To understand how nabiximols works, we must first explore the endocannabinoid system—a widespread neuromodulatory network that plays a crucial role in central nervous system function, immune processes, and maintaining biological balance. This system comprises:
(CB1 and CB2) distributed throughout the body, including in the central and peripheral nervous systems and peripheral organs
Produced naturally by our bodies to maintain physiological balance
That synthesize and degrade these cannabinoids to regulate their activity
Nabiximols works by mimicking our natural endocannabinoids, binding to these receptors and modulating their activity. CB1 receptors are primarily found in the brain and central nervous system, while CB2 receptors are more abundant in immune cells. This distribution explains why cannabinoids can impact both neurological symptoms like spasticity and immune function in MS 4 .
Key Insight: The concept of "spasticity-plus syndrome" has emerged to explain why nabiximols often improves multiple symptoms simultaneously—including pain, sleep disturbances, and bladder dysfunction—suggesting these symptoms may share common underlying pathways that cannabinoids can modulate 1 7 .
In 2018, a landmark study revealed that nabiximols doesn't just relieve symptoms—it fundamentally influences gene expression patterns in our immune systems 4 . Researchers performed whole-genome expression profiling in blood samples from 33 MS patients before and after 4 weeks of nabiximols treatment.
The findings were striking: treatment responders showed significant downregulation of immune-related pathways after nabiximols treatment. This suggests the drug calms the overactive immune response characteristic of MS. Network analysis identified key hub molecules functionally related to the immune system, including:
| Pathway Category | Specific Pathways Affected | Biological Significance |
|---|---|---|
| Inflammatory Signaling | Cytokine-cytokine receptor interaction | Regulates communication between immune cells |
| Immune Cell Activation | T-cell receptor signaling | Controls adaptive immune responses |
| Cell Survival & Proliferation | Apoptosis pathways | Influences programmed cell death |
| Stress Response | MAPK signaling | Mediates cellular response to stressors |
More recently, researchers have discovered that specific genetic variations can predict whether a patient will respond to nabiximols 5 . This field, known as pharmacogenetics, examines how our DNA affects our response to drugs.
In an exploratory genetic study, scientists analyzed 45 MS patients treated with nabiximols, comparing genetic profiles between responders and non-responders. The results were revealing: variations in the ABCB1 gene—which encodes P-glycoprotein, an efflux pump that transports substances including THC and CBD out of cells—were significantly associated with treatment response.
Specifically, patients carrying the T allele in either of two ABCB1 single nucleotide polymorphisms (SNPs)—rs1128503 (1236 C>T) and rs1045642 (3435 A>T)—showed dramatically better responses to nabiximols. These genetic variations reduce P-glycoprotein efflux activity, potentially allowing more active drug to reach its target sites.
| Gene | SNP Identifier | Function | Response Association |
|---|---|---|---|
| ABCB1 | rs1128503 (1236 C>T) | Encodes drug transporter P-glycoprotein | T allele predictive of better response |
| ABCB1 | rs1045642 (3435 A>T) | Encodes drug transporter P-glycoprotein | T allele predictive of better response |
| CNR1 | rs1049353 | Encodes cannabinoid receptor 1 | No significant association |
| CNR2 | rs2501431 | Encodes cannabinoid receptor 2 | No significant association |
| CYP2C9 | rs1799853 | Metabolizes cannabinoids | No significant association |
| CYP2C19 | rs4244285 | Metabolizes cannabinoids | No significant association |
The 2018 study that first identified nabiximols' effect on gene networks employed a rigorous approach 4 :
33 MS patients with spasticity were enrolled, all of whom began nabiximols treatment according to standard protocols.
Whole blood samples were collected from each patient at two time points: immediately before starting treatment (baseline) and after 4 weeks of continuous nabiximols use.
Researchers isolated RNA from all blood samples, preserving the gene expression profiles at each time point.
Using advanced gene chip technology, the team measured the expression levels of thousands of genes simultaneously, creating a comprehensive snapshot of which genes were active or suppressed.
After 4 weeks of treatment, patients were classified as responders (n=19) or non-responders (n=14) based on their clinical improvement in spasticity symptoms.
Sophisticated computational tools identified differentially expressed genes between baseline and week 4, and between responder groups. Pathway and network analyses interpreted these gene expression changes in the context of biological systems.
MS Patients
Responders
Non-responders
Weeks Treatment
The analysis revealed that nabiximols treatment led to modest but important changes in gene expression across multiple immune pathways. When researchers focused specifically on treatment responders, these changes became more pronounced, suggesting that clinical improvement correlates with specific genetic modulation.
Network analysis identified several hub genes that appear crucial to nabiximols' mechanism of action. These hub genes function as key regulators in cellular networks—when their expression changes, it creates ripple effects throughout interconnected biological pathways.
| Clinical Measure | Responders (n=19) | Non-responders (n=14) | Statistical Significance |
|---|---|---|---|
| Spasticity Improvement | Significant | Minimal | p < 0.05 |
| Immune Pathway Downregulation | Pronounced | Minimal | p < 0.05 |
| Pain Reduction | Substantial | Minimal | Not reported |
| Sleep Improvement | Substantial | Minimal | Not reported |
Follow-up laboratory experiments confirmed these findings. When researchers exposed immune cells from MS patients to pro-inflammatory agents in the presence of cannabinoids, they observed reduced inflammatory responses, supporting the immunomodulatory properties suggested by the gene expression data 4 .
Understanding nabiximols' effects on gene networks requires specialized research tools. Here are the key components used in these groundbreaking studies:
| Research Tool | Function in Research | Application in Nabiximols Studies |
|---|---|---|
| Whole-genome microarrays | Simultaneously measures expression of thousands of genes | Identifying differentially expressed genes after treatment |
| RNA extraction kits | Isolates and purifies RNA from blood or tissue samples | Preparing genetic material for expression analysis |
| TaqMan genotyping assays | Detects specific genetic variations (SNPs) | Determining ABCB1 and other pharmacogenetic variants |
| Peripheral blood mononuclear cells (PBMCs) | Immune cells used for in vitro experiments | Testing immunomodulatory effects of cannabinoids |
| Pathway analysis software | Interprets gene expression data in biological context | Identifying affected immune pathways and networks |
| ELISA kits | Measures protein levels of inflammatory markers | Validating gene expression findings at protein level |
The implications of these genetic findings are profound. We're moving toward a future where a simple genetic test could determine whether a patient is likely to respond to nabiximols, sparing non-responders the frustration of ineffective treatment while quickly providing relief to those who will benefit.
This research also opens new avenues for drug development. By understanding exactly which pathways nabiximols modulates, scientists can develop more targeted therapies with potentially fewer side effects. The discovered hub genes might themselves become targets for future MS treatments.
As research continues to unravel the complex relationship between our genes and cannabis-based medicines, we stand at the threshold of a new era in multiple sclerosis management—one where treatments are increasingly tailored to the individual's unique genetic makeup, maximizing effectiveness while minimizing unnecessary side effects.
The green revolution in MS therapy is well underway, and it's being guided by the very blueprint of life itself—our DNA.
Predict treatment response before prescription
Develop drugs based on genetic pathways
Optimize treatment based on individual genetics
Incorporate genetics into treatment protocols