top of page

Cannabis Neuroscience - Charlotte’s Web

The moving stories of the parents who gave their children cannabis to save their lives

Girl with EEG electrodes attached to her head.
Shutterstock image 1446875396 by vasara.

Today is April 20, a day when many people celebrate the wonderful properties of cannabis.

For the last few days, I have been publishing one article a day about the neuroscience of cannabis and the endocannabinoid system:

I heard the moving story of Charlotte Figi and Charlotte’s Web in the opening talk at the Winter Conference in Brain Research (WCBR), an annual meeting of neuroscientists held at a ski resort in North America. The talk was given by one of the scientists who found the connection between cannabis and epilepsy.

Dravet Syndrome

Dravet Syndrome is an epileptic disorder in children of genetic origin. The seizures are unpredictable, but often triggered by heat. It’s so severe that sometimes it can lead to death. It typically appears when the child is 6 months old and becomes worse as the child ages.

Their seizures are terribly debilitating. Apart from them, the children affected show motor problems, autism, hyperactivity, impulsivity, somnolence and insomnia. These problems, together with the fact that a seizure represents a mortal danger, makes impossible for the child to attend school. He or she requires constant attention.

It’s hard to imagine what it must be like to be the parent of a child with this disease.

The story of Charlotte

One of these children was a little girl named Charlotte Figi, who lived with her parents in Colorado. She had a twin named Chase, who was healthy. They were born on October 18, 2006.

Charlotte’s seizures started when she was 3 months old. The first one lasted 30 minutes. Over the next few months, Charlotte had seizures lasting two to four hours. She was hospitalized, but the doctors could not find what was wrong with her. They put her on benzodiazepines and barbiturates, drugs that affect normal behavior and are addictive. Maybe it was these drugs, maybe it was the seizures, but by age two Charlotte started to decline cognitively.

When she was two and a half, the doctors were finally able to diagnose her. She had the Scn1a mutation in the gene that encodes for the Nav1.1 voltage-gated sodium channel, one of the proteins in the axons of neurons that mediate action potentials. The Scn1a mutation is present in 80% of the cases of Dravet Syndrome.

A Dravet specialist put Charlotte in a ketonic diet, because high levels of ketones suppress seizures. But they also caused bone loss and weakened Charlotte’s immune system. And then, after two years, the seizures came back.

Charlotte’s father, Matt, looked on the internet for solutions. He found a boy in California with Dravet Syndrome who was being successfully treated with cannabis.

At age 5, Charlotte couldn’t walk, talk or eat. She was having 300 seizures a week. She was taken to the hospital several times at the edge of death.

Her parents hesitated to give her cannabis. Scientists had been cautioning parents that cannabis had nasty effects on the developing bodies of children, affecting the lungs, the heart and the brain.

They consulted two more specialists. But, since Charlotte was at the edge of death, they finally decided to give her cannabis. They found a strain of marijuana called R4, which was low in THC and high on CBD. They gave it to Charlotte.

Her seizures went away for seven days.

The Charlotte’s Web strain of cannabis

Looking for a consistent supply of cannabis with low THC and high CBD, Charlotte’s parents met the Stanley brothers, Joel, Jesse, Jon, Jordan, Jared and Josh, who were one of the largest legal growers of cannabis in Colorado. They had developed a strain of marijuana with low THC content and high in CBD. Because it didn’t get people high, they couldn’t sell it, so they initially called it Hippie’s Disappointment.

When they saw what it did to Charlotte, they renamed it Charlotte’s Web, after the popular children’s book and little Charlotte.

By age 6, Charlotte was thriving. She was walking and riding her bike. For the first time in years, her parents heard her laugh. Her seizures happened only two or three times per months, mostly while she slept.

The Stanley brothers started the Realm of Caring Foundation, a non-profit dedicated to provide special strains of cannabis to children suffering from Dravet Syndrome, and also to adults suffering from Parkinson’s Disease, multiple sclerosis, epilepsy and cancer.

It was 2012. Cannabis was already legal in many states of the USA, but moving it from one state to another was still illegal under federal law. That meant that you could not buy Charlotte’s Web outside Colorado. Parents of children with Dravet Syndrome starting moving to Colorado, so they could give their children the life-saving Charlotte’s Web strain of cannabis (Whiting et al., 2015).

Unfortunately, Charlotte’s story doesn’t have a happy ending. She died of pneumonia with complications related to her disease on April 7, 2020.

The neuroscience

However, the connection between CBD and the mutated Nav1.1 sodium channel that causes Dravet Syndrome was still unknown. It was important to find it in order to give the treatment of children with cannabis a solid scientific basis. Besides, unraveling such a mechanism could lead to the discovery of other drugs to treat epilepsy.

A team of scientist from the University of Washington in Seattle set to work on this (Kaplan et al., 2017). The first thing they did was to find a strain of mice with the mutation Scn1a, so that the mice would have the same defective Nav1.1 sodium channel as the children with Dravet Syndrome. These mice had epileptic seizures triggered by heat and deficits in social behavior that resemble autism.

Previous work had shown that the Scn1a mutation caused the Nav1.1 sodium channels to stop working. These Nav1.1 channels are present in neurons that release the neurotransmitter GABA (GABAergic interneurons), which inhibits other neurons. When the GABAergic interneurons do not fire enough action potentials, they cannot oppose the build-up of excitation in the brain, and an epileptic attack ensues.

When Kaplan et al. gave CBD to the mice with the Scn1a mutation, the severity, duration and number of their seizures were significantly decreased. CBD also reduced the autistic-like social behavior of the mutant mice. Moreover, CBD increased the excitability of the GABAergic interneurons in the hippocampus of the mutant mice, a part of the brain essential for memory formation and that is the origin of epileptic seizures.

The effect of CBD was not mediated by CB1 receptors, which are the receptors responsible for the psychotropic effects of THC. Blocking CB1 receptors with their inverse agonist AM281 did not affect the increase in the activity of the GABAergic interneurons produced by CBD. However, blocking GPR55, the third cannabinoid receptor, with its antagonist CID16020046 increased the activity of the GABAergic interneurons, just like CBD. CBD did not increase the excitability of GABAergic interneurons over the increase already produced by the GPR55 antagonist.

The investigators concluded that the effect of CBD was mediated by the cannabinoid receptor GPR55. What CBD does is to inhibit GPR55 because is an antagonist of these receptors. GPR55 receptors inhibit Nav1.1 channels. When CBD blocks GPR55, this restores the function of Nav1.1 channels, preventing the epileptic attacks in Dravet syndrome.

Epidiolex: a new drug to treat Dravet Syndrome

CBD is now sold as an oral solution by GW Pharmaceuticals as Epidiolex ™ (Gray and Whalley, 2020). It was approved by the Food and Drug Administration in 2018 to treat Dravet Syndrome and other epileptic disorders. In September 2019, it was approved for European consumption as Epidyolex.

The parents of children with Dravet Syndrome no longer have to relocate to Colorado to buy Charlotte’s Web for their children. They can just give them Epidiolex.

If President Nixon would not have declared cannabis a Schedule I drug with no therapeutic use for political reasons, the use of CBD to treat Dravet Syndrome may have been discovered much sooner. Perhaps even before Charlotte was born.

References

  • Gray RA, Whalley BJ (2020) The proposed mechanisms of action of CBD in epilepsy. Epileptic Disord 22:10-15.

  • Kaplan JS, Stella N, Catterall WA, Westenbroek RE (2017) Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A 114:11229-11234.

  • Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J (2015) Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. Jama 313:2456-2473.

Commentaires


bottom of page