Spasticity Relief From Cannabinoids Works Through CB1 Receptors, Not CB2, in MS Mouse Models | Research

The takeaway

Using gene-knockout mice, researchers proved that the anti-spastic effects of cannabinoids depend entirely on CB1 receptors, meaning therapeutic and psychoactive effects cannot be easily separated.

Read this if you want to understand why cannabis medicines for spasticity inevitably involve some psychoactive effects.

CB1-knockout mice showed zero anti-spastic response to any cannabinoid tested

What the researchers found

Researchers tested cannabinoid effects on spasticity in both normal mice and mice genetically lacking CB1 receptors, all with experimental autoimmune encephalomyelitis (a model of MS).

Some CB2-selective agonists (like RWJ400065) appeared to reduce spasticity. However, when tested in CB1-deficient mice, this anti-spastic effect completely disappeared, revealing that the seeming "CB2" effect was actually due to cross-reactivity with CB1 receptors.

Non-selective cannabinoid agonists (WIN55,212-2 and CP55,940) also lost their anti-spastic effects in CB1-knockout mice. This provided definitive genetic evidence that CB1, not CB2, is the receptor responsible for cannabinoid control of spasticity.

The authors noted a significant clinical implication: since CB1 also mediates the psychoactive effects of cannabinoids, truly separating therapeutic anti-spastic effects from unwanted psychological effects would be difficult.

Why it matters

There had been hope that CB2-selective drugs could provide the anti-spastic benefits of cannabinoids without psychoactive side effects. This study eliminated that possibility for spasticity, showing that even apparently CB2-selective drugs worked through CB1 cross-reactivity.

The numbers in context

RWJ400065 (CB2-selective agonist) reduced spasticity in wildtype mice but had zero effect in CB1-knockout mice. WIN55,212-2 and CP55,940 (non-selective agonists) also lost anti-spastic effects in CB1-deficient mice.

How the study worked

Spasticity was induced in wildtype and CB1-deficient mice through relapsing experimental autoimmune encephalomyelitis. Hindlimb spastic stiffness was measured by resistance to flexion against a strain gauge following administration of various CB1 and CB2 receptor agonists.

What this study cannot tell us

Mouse models of MS do not fully replicate human MS spasticity. The limited specificity of available cannabinoid compounds was acknowledged by the authors. Genetic knockout models can develop compensatory changes that might affect results.

How to read the evidence

This animal study used gene-knockout technology to provide definitive receptor-level evidence, which is strong for mechanistic understanding but requires caution in human translation.

When this study was published

Published in 2007. This finding has been confirmed by subsequent research and has influenced the development of cannabis-based medicines for MS.

The bigger picture

This study clarified a fundamental question in cannabinoid pharmacology: which receptor controls spasticity? The answer (CB1) has important implications for drug development, as it means anti-spastic cannabinoid medicines will inevitably carry some risk of psychoactive side effects.

Questions still open

Could partial CB1 agonists or allosteric modulators provide anti-spastic effects with reduced psychoactivity? Are there ways to target CB1 receptors in the spinal cord preferentially to minimize brain-mediated side effects?

Common questions

What are CB1 and CB2 receptors?

CB1 receptors are found primarily in the brain and nervous system and mediate most of cannabis's psychoactive effects. CB2 receptors are found mainly on immune cells. Researchers hoped CB2-selective drugs could be therapeutic without being psychoactive.

Does this mean MS patients can't avoid the "high" from cannabis medicine?

The study suggests it's difficult to fully separate the anti-spastic effects from psychoactive effects because both use CB1 receptors. However, careful dosing and formulations like Sativex (which includes CBD) can minimize psychoactive effects.

Read the original research

Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors.

British journal of pharmacology, 150(4), 519-25

View on PubMed ↗

Citation

Pryce, G; Baker, D. (2007). Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors.. British journal of pharmacology, 150(4), 519-25.