Multiple FAAH inhibitors reduced spasticity in a mouse model of MS by boosting endocannabinoid levels, without causing the sedation and psychoactive effects seen with cannabis, and the effect was definitively confirmed using genetic knockout mice.
Read this if you have MS spasticity and are interested in endocannabinoid-based treatments without cannabis side effects.
Anti-spastic effect confirmed by loss in FAAH-deficient mice, the gold standard for target validation
What the researchers found
Mice with experimental autoimmune encephalomyelitis (EAE, a model of MS) developed spasticity that was treated with three different FAAH inhibitors (CAY100400, CAY100402, URB597). All reduced limb stiffness as measured by strain gauge. The anti-spastic effect was sustained with repeated dosing.
Critically, the therapeutic effect was absent in FAAH-deficient mice, definitively proving that the drugs work specifically through FAAH inhibition rather than off-target effects. The MAGL inhibitor JZL184 also controlled spasticity. Importantly, anti-spastic effects occurred at doses that did not produce overt cannabinoid-like behavioral effects (sedation, catalepsy, hypothermia).
Why it matters
Cannabis extracts treat MS spasticity (Sativex is approved) but have dose-limiting side effects. FAAH inhibitors achieve the same anti-spastic effect by boosting the body's own endocannabinoids, avoiding the psychoactive side effects. This study provided definitive proof-of-concept for a new class of anti-spasticity drugs.
The numbers in context
3 FAAH inhibitors tested: all reduced spasticity. Effect sustained with repeated dosing. Effect absent in FAAH-deficient mice (definitive target validation). MAGL inhibitor JZL184 also effective. No overt cannabimimetic side effects at therapeutic doses.
How the study worked
EAE model in Biozzi ABH mice (wild-type and FAAH-deficient). Limb stiffness measured by strain gauge. Three FAAH inhibitors and one MAGL inhibitor tested. FAAH-deficient mice used to confirm target specificity. Repeated dosing to assess sustained efficacy.
What this study cannot tell us
Mouse EAE model does not perfectly replicate human MS spasticity. The FAAH inhibitors tested have not been clinically developed for MS. Long-term effects and safety profiles are unknown. The transition from animal models to human MS is historically challenging.
How to read the evidence
Preclinical study with definitive genetic validation; moderate-strong evidence for FAAH as an anti-spasticity target.
When this study was published
Published in 2013. FAAH inhibitor development continues for multiple indications.
The bigger picture
This study establishes FAAH inhibitors as a potential new class of MS medications that harness the endocannabinoid system's anti-spastic properties without the limitations of cannabis. The genetic validation (loss of effect in FAAH knockouts) provides the strongest possible preclinical evidence for the target.
Questions still open
- Would FAAH inhibitors be effective in human MS spasticity? How do they compare head-to-head with Sativex? Could they be combined with existing anti-spasticity medications? What is the long-term safety profile?
Common questions
Could FAAH inhibitors replace cannabis for MS spasticity?
How is this different from Sativex?
Read the original research
Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors.
Multiple sclerosis (Houndmills, Basingstoke, England), 19(14), 1896-904
Citation
Pryce, G; Cabranes, A; Fernández-Ruiz, J; Bisogno, T; Di Marzo, V; Long, J Z; Cravatt, B F; Giovannoni, G; Baker, D. (2013). Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors.. Multiple sclerosis (Houndmills, Basingstoke, England), 19(14), 1896-904. https://doi.org/10.1177/1352458513485982
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