Scientists found a cannabinoid-inspired drug that controls muscle spasticity without causing sedation | Research

The takeaway

A compound originally designed as an anandamide analog controlled spasticity in a multiple sclerosis mouse model by opening potassium channels in neurons, without affecting normal muscle tone or causing sedation.

Read this if you want to see how cannabinoid research led to an unexpected discovery about controlling spasticity.

1,000-fold therapeutic window: effective spasticity control without sedation

What the researchers found

VSN16R, designed as an analog of the endocannabinoid anandamide, controlled spasticity in a mouse model of multiple sclerosis (experimental encephalomyelitis) with a therapeutic window over 1,000-fold, meaning effective doses were far below those causing side effects.

Surprisingly, VSN16R did not work through the known cannabinoid receptors (CB1, CB2, or GPR55). Instead, it activated the neuronal form of big conductance calcium-activated potassium (BKCa) channels. Opening these channels hyperpolarized neurons, reducing the excessive neural excitability that causes spasticity.

The compound was effective at plasma levels achievable and safe in humans, and it did not affect normal muscle tone, only reducing the excessive tone that defines spasticity.

Why it matters

Cannabis-based treatments for MS spasticity exist (Sativex) but cause sedation and intoxication through CB1 activation. This study identified a new target, the BKCa channel, discovered through cannabinoid-inspired drug design, that could control spasticity without these central nervous system side effects.

The numbers in context

Therapeutic window: over 1,000-fold between effective and side effect-producing doses. VSN16R showed nanomolar activity in functional assays. Dose-dependent inhibition of spasticity in the EAE mouse model. No binding to CB1, CB2, or GPR55 receptors.

How the study worked

Multi-method approach including chemical synthesis, receptor binding assays, electrophysiology, tissue-based functional assays, and in vivo testing in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS. Toxicological and safety studies were performed in both animals and humans.

What this study cannot tell us

Preclinical study with limited human safety data at time of publication. The EAE mouse model does not fully replicate human MS spasticity. Whether the same BKCa-mediated effect translates to human neurons and spasticity remains to be confirmed in clinical trials. Long-term safety and efficacy data are not available.

How to read the evidence

Preclinical study with animal efficacy data and preliminary human safety testing. Promising early-stage research but not yet validated in clinical trials.

When this study was published

Published in 2017. VSN16R represents an ongoing approach to separating therapeutic benefits from intoxicating effects in cannabinoid-derived medicine.

The bigger picture

This is a case where cannabinoid science led to a completely unexpected discovery. Starting from the structure of anandamide, researchers found a compound that does not work through cannabinoid receptors at all but instead revealed a new mechanism for controlling neural excitability. The BKCa channel could become a drug target for spasticity and potentially other conditions involving excessive neural firing.

Questions still open

How far has VSN16R progressed in clinical development since this publication? Could BKCa channel openers treat other conditions characterized by neural hyperexcitability, such as epilepsy or neuropathic pain? Does cannabis itself activate BKCa channels as part of its anti-spasticity effects?

Common questions

Is this a cannabis-based medicine?

VSN16R was designed starting from the structure of anandamide (the body's own cannabinoid), but it turned out to work through an entirely different mechanism than cannabis. It does not activate cannabinoid receptors and does not cause intoxication or sedation.

How is this different from Sativex for MS?

Sativex is a cannabis extract containing both THC and CBD that works through CB1 and CB2 receptors. It helps with spasticity but causes sedation and intoxication. VSN16R controls spasticity through potassium channels without these central nervous system effects, offering a much wider safety margin.

Read the original research

Big conductance calcium-activated potassium channel openers control spasticity without sedation.

British journal of pharmacology, 174(16), 2662-2681

View on PubMed ↗Publisher’s paper ↗

Citation

Baker, David; Pryce, Gareth; Visintin, Cristina; Sisay, Sofia; Bondarenko, Alexander I; Vanessa Ho, W S; Jackson, Samuel J; Williams, Thomas E; Al-Izki, Sarah; Sevastou, Ioanna; Okuyama, Masahiro; Graier, Wolfgang F; Stevenson, Lesley A; Tanner, Carolyn; Ross, Ruth; Pertwee, Roger G; Henstridge, Christopher M; Irving, Andrew J; Schulman, Jesse; Powell, Keith; Baker, Mark D; Giovannoni, Gavin; Selwood, David L. (2017). Big conductance calcium-activated potassium channel openers control spasticity without sedation.. British journal of pharmacology, 174(16), 2662-2681. https://doi.org/10.1111/bph.13889