FAAH Inhibitors Reduced MS-Like Spasticity in Mice Without Cannabis-Like Side Effects
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.
Quick Facts
What This Study 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).
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- Anti-spastic effect confirmed by loss in FAAH-deficient mice, the gold standard for target validation
- Evidence Grade:
- Preclinical study with definitive genetic validation; moderate-strong evidence for FAAH as an anti-spasticity target.
- Study Age:
- Published in 2013. FAAH inhibitor development continues for multiple indications.
- Original Title:
- Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors.
- Published In:
- Multiple sclerosis (Houndmills, Basingstoke, England), 19(14), 1896-904 (2013)
- Authors:
- Pryce, G(5), Cabranes, A, Fernández-Ruiz, J, Bisogno, T, Di Marzo, V, Long, J Z, Cravatt, B F, Giovannoni, G, Baker, D
- Database ID:
- RTHC-00721
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Could FAAH inhibitors replace cannabis for MS spasticity?
This mouse study suggests they could. FAAH inhibitors reduced spasticity as effectively as cannabis-based treatments but without psychoactive side effects. They work by boosting the body's own endocannabinoids rather than flooding the system with external cannabinoids. However, this has not yet been demonstrated in human MS patients.
How is this different from Sativex?
Sativex delivers external THC and CBD, which can cause dizziness and sedation. FAAH inhibitors boost the body's own endocannabinoid (anandamide) by preventing its breakdown. This approach is more targeted and produced anti-spastic effects at doses that did not cause cannabis-like behavioral effects in the mice studied.
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Cite This Study
https://rethinkthc.com/research/RTHC-00721APA
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
MLA
Pryce, G, et al. "Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors.." Multiple sclerosis (Houndmills, 2013. https://doi.org/10.1177/1352458513485982
RethinkTHC
RethinkTHC Research Database. "Control of experimental spasticity by targeting the degradat..." RTHC-00721. Retrieved from https://rethinkthc.com/research/pryce-2013-control-of-experimental-spasticity
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.