Genetic Clues May Predict Cannabis-Based Treatment Success in Multiple Sclerosis

In the quest to personalize therapy for multiple sclerosis (MS), a new study suggests that common genetic variants in drug transporter genes may predict how well patients respond to nabiximols, a cannabinoid-based medication used to relieve MS-related spasticity.

Published in the Journal of Cannabis Research, the exploratory study investigated whether single nucleotide polymorphisms (SNPs) could help explain why only 60 to 70 percent of patients benefit from nabiximols, an oromucosal spray containing a 1:1 ratio of tetrahydrocannabinol (THC) and cannabidiol (CBD).

Researchers analyzed 45 MS patients treated with nabiximols over a 10-year period at a single Italian center. Patients were categorized as "responders" or "non-responders" based on whether their spasticity symptoms improved by at least 30 percent on a standardized numeric rating scale after four weeks of therapy. Importantly, all participants were receiving nabiximols as monotherapy and were not using other medications that might influence drug metabolism or pain perception, allowing the investigators to isolate potential genetic effects.

The team focused on genetic variants in key genes involved in cannabinoid pharmacodynamics and pharmacokinetics: the cannabinoid receptor genes CNR1 and CNR2, the cytochrome P450 enzymes CYP2C9 and CYP2C19, and the efflux transporter gene ABCB1, which encodes P-glycoprotein. This transporter is known to influence drug distribution across the blood-brain barrier and has previously been implicated in variable responses to pain medications and cannabinoids.

The most striking findings came from two SNPs in ABCB1: rs1128503 and rs1045642. Patients who were homozygous for the T allele in these polymorphisms were significantly more likely to respond to nabiximols. Specifically, none of the non-responders had the T/T genotype for either SNP, while about 38 to 48 percent of responders did. The presence of the T allele was associated with a dramatically higher likelihood of treatment success—odds ratios of 20.5 and 30.9 for rs1128503 and rs1045642, respectively.

These T alleles have previously been linked to reduced P-glycoprotein activity, suggesting a plausible mechanism: decreased efflux of THC and CBD from the brain could enhance drug exposure at its site of action, thereby improving symptom control.

In contrast, no significant associations were found between treatment response and polymorphisms in the cannabinoid receptor genes or cytochrome P450 enzymes, despite their known roles in cannabinoid signaling and metabolism. The authors speculated that either the selected SNPs in these genes do not have a strong enough functional effect at clinical doses, or that compensatory pathways—such as serotonin or TRP channels—may dilute the influence of receptor-level genetic variation.

The findings echo a growing body of evidence linking ABCB1 variants to altered responses to cannabinoids in other settings, including epilepsy and chronic pain management. Still, more research is needed to understand how these genetic differences might interact with dosage, formulation, and comorbidities in real-world settings.

As cannabinoid therapeutics become more prevalent, the integration of pharmacogenomics into clinical decision-making could offer a powerful tool for maximizing benefits and minimizing adverse effects—particularly in complex neuroinflammatory disorders like MS, where treatment responses are notoriously heterogeneous.