Synthetic CBD derivative prevents seizures in mice without causing sedation

A new synthetic derivative of cannabidiol, or CBD, reduces seizure severity and promotes healthy brain cell development in mice. The compound, modified to have an elongated chemical tail, protected against chemically induced seizures without causing sedation. The research was published in the journal Neuropsychopharmacology.

Developmental epilepsy syndromes are rare genetic disorders characterized by recurrent seizures and developmental delays in children. A common feature of these syndromes is a lack of inhibitory control over brain cell activity. The primary medications used to treat these conditions are benzodiazepines, which act to slow down the nervous system and decrease brain excitability.

Chronic use of these medications can lead to rapid tolerance and physical dependence. These drugs can also cause adverse side effects in children, including sleepiness, breathing problems, and cognitive deficits.

Cannabidiol, a major compound found in the cannabis plant, has emerged as a potential alternative to traditional anti-seizure medications. Unlike THC, the psychoactive component of cannabis, CBD does not produce a high. The Food and Drug Administration has approved a purified CBD solution to treat a few specific rare seizure disorders. The broader use of natural CBD for other types of epilepsy remains limited, and researchers are looking for ways to improve upon the natural molecule.

Researchers led by Dustin J. Hines and Rochelle M. Hines of the University of Nevada Las Vegas sought to design a library of new synthetic CBD derivatives. They started with a compound called carvone, an extract from caraway seeds, rather than natural cannabis extracts. This method avoids any potential THC contamination.

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The researchers created several different variations of synthetic CBD by altering a specific part of the molecular structure called the alkyl side chain. This chain is a tail of carbon atoms attached to the main ring of the molecule. The team hypothesized that lengthening this carbon chain might change how the compound interacts with brain receptors.

To see how these structural changes affect brain activity, the researchers conducted a small study in freely moving mice. They gave the animals various synthetic CBD molecules with carbon chain lengths ranging from three to eight atoms. The researchers then measured the animals’ brain waves using electroencephalography, or EEG. Brain waves are electrical impulses that neurons use to communicate. They are divided into different frequency bands, such as delta, theta, and beta.

The researchers found that modifying the length of the carbon chain produced distinct effects on the animals’ brain wave frequencies. The molecule with an eight-carbon chain, named (+)-CBD-oct, increased electrical power specifically in the delta and theta frequency bands. Delta and theta are low-frequency brain waves often associated with deep relaxation, sleep, and memory processing. Based on this unique brain wave profile, the researchers selected (+)-CBD-oct as their primary candidate to test as an anti-seizure medication.

Because many epilepsy treatments cause severe sleepiness, the researchers tested whether (+)-CBD-oct would sedate the animals. They gave adult mice either a water placebo or a dose of the synthetic compound. The animals were then placed in an open testing arena for one hour, and researchers tracked the animals’ movements using video analysis software.

Mice treated with (+)-CBD-oct explored the open arena at similar speeds and traveled similar total distances compared to the mice that received the placebo. The synthetic compound did not reduce exploration or produce acute sedative effects. This lack of sedation distinguished the new compound from traditional benzodiazepines.

The team then tested the compound’s ability to stop seizures in normal adult mice. They gave the animals either a placebo, natural CBD, or the synthetic (+)-CBD-oct. Thirty minutes later, the researchers injected the mice with kainate. Kainate is a chemical compound routinely used in laboratories to induce seizures. They monitored the mice for physical signs of seizures and recorded their brain activity using EEG.

Mice pre-treated with (+)-CBD-oct experienced much less intense seizures than those given the placebo or natural CBD. The synthetic compound increased the amount of time it took for the first seizure to begin. The treatment also lowered the electrical peak of the seizure events measured on the EEG. The kainate injection caused high mortality in the placebo group, but (+)-CBD-oct treatment prevented mortality.

To see if the drug worked in a disease model, the researchers repeated the seizure experiment using a genetically modified mouse. This specific mouse model has a genetic mutation that disrupts normal inhibitory control in the brain. The mutation makes the mice highly susceptible to spontaneous seizures and sensitive to seizure-inducing chemicals, mimicking aspects of human developmental epilepsy.

The researchers gave these mutant mice (+)-CBD-oct or a placebo before injecting them with kainate. The synthetic compound reduced the behavioral signs of seizure severity in the mutant mice. The treatment delayed the onset of the seizures and reduced the total number of seizure events. The compound also improved the survival rate of the mutant animals following the chemical injection.

Finally, the researchers investigated how the compound affects the developing brain. Standard anti-seizure drugs can alter the growth of dendritic spines. Dendritic spines are tiny protrusions on the surface of brain cells that help form electrical connections with other neurons. The researchers administered (+)-CBD-oct or a placebo to normal mouse pups and the mutant epilepsy mouse pups for five consecutive days.

After the treatment period, they examined the brain tissue under a microscope. The drug did not alter or reduce the brain cell connections in the normal mice. The mutant mice normally display an overabundance of immature dendritic spines in their brains.

The five-day treatment normalized the brain cell structures in the mutant mice. The compound reduced the number of abnormal, immature connections in both the cortex and hippocampus, and promoted the development of mature dendritic spines in the cortex.

The study relied on a single chemical agent, kainate, to induce seizures. This specific chemical model may not capture the full range of biological mechanisms present in different types of human epilepsy. The researchers conducted the experiments using small groups of animals, and the study only examined male mice for the adult seizure tests. It is currently unknown if female adult mice would respond to the treatment in the same way.

The exact mechanisms by which the synthetic compound stops seizures remain uncharacterized. The drug altered the physical shape of the brain cell connections, but the researchers did not examine whether this physical change improved the functional electrical activity at the synapses. Future research will need to determine exactly which cell receptors the compound targets to exert its protective effects.

The study, “Carvone derived cannabidiol enantiomers as novel anticonvulsants,” was authored by Rochelle M. Hines, April Contreras, Adriana Carrillo, Alexandra Paton, Antonio J. Tenorio, William A. Maio, and Dustin J. Hines.