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Three Rare Cannabinoids May Help to Stop Seizures, Study Suggests

By Alexander Beadle

Published: Oct 12, 2021   
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The properties of three lesser-known cannabinoids may help to explain why cannabis extracts can be an effective treatment for epilepsy, say pharmacologists at the University of Sydney.

In a new study, researchers screened seven different cannabinoids and found three – cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), and cannabigerovarinic acid (CBGVA) – to have significant anticonvulsant effects in a mouse model of drug-resistant epilepsy. The study, which was published in the British Journal of Pharmacology, found that CBGA was the most potent of the three and may also affect many of the same therapeutic targets that are targeted by traditional anti-epilepsy drugs.

This study forms part of a larger research program in the Lambert Initiative for Cannabinoid Therapeutics research group at the University of Sydney. The group is currently looking to systematically test individual components of cannabis to identify those which might be helpful in combating seizures, in order to examine how these components might work together beneficially in broad-spectrum cannabis oils.

CBGA, CBGVA, and CBDVA reduce seizures in mice

CBGA, CBGVA, and CBDVA are all cannabinoid acids that are present in raw cannabis. When heat is applied to cannabis flower during smoking or vaping, CBGVA and CBDVA are both decarboxylated to form the minor cannabinoids CBGV and CBDV, respectively.

CBGA is slightly more complicated. It is commonly nicknamed “the mother of all cannabinoids” on account of it being the precursor compound to many of the most prominent and well-known cannabinoids, such as CBD and THC. As the cannabis plant matures, various enzymes within the plant material convert CBGA into these major cannabinoids, with any remainder becoming CBG after heating.

“The cannabinoid acids are abundant in cannabis but have received much less scientific attention. We are just beginning to understand their therapeutic potential,” explained associate professor Jonathon Arnold of the Lambert Initiative for Cannabinoid Therapeutics, in a statement.

A mouse model of Dravet syndrome – a rare form of intractable epilepsy – was used in this study to test the anti-seizure effect of these cannabinoids. CBGA, CBGVA, and CBDVA were all found to exhibit some anticonvulsant properties, and CBGVA and CBDVA significantly elevated the temperature required to trigger thermally-induced seizures in the mice.

CBGA had the most potent anti-seizure effect, with thermally-induced seizures and spontaneous seizures being suppressed in a clearly dose-dependent manner. Notably, CBGA appeared to be even more potent than CBD for this purpose, which has been previously approved for use by the FDA in the treatment of Dravet syndrome. CBGA also demonstrated anticonvulsant activity when used in a standard maximal electroshock seizure (MES) threshold test, which was done in order to test the efficacy of the drug on generalized tonic-clonic seizures.

CGBA can also be pro-convulsant in some cases

In contrast, CBGA was found to be pro-convulsant in the conventional 6-Hz threshold test for focal or psychomotor seizures. High doses of CBGA were also associated with an increased frequency of spontaneous seizures in the study mice. This would imply that, unlike CBD, which is known to be broadly effective as an anticonvulsant against many different types of seizures, CBGA may only be useful in the case of generalized tonic-clonic seizures.

“We found that CBGA was more potent than CBD in reducing seizures triggered by a febrile event in a mouse model of Dravet syndrome,” said lead author Dr Lyndsey Anderson, a preclinical pharmacologist with the Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney.

“Although higher doses of CBGA also had proconvulsant effects on other seizure types highlighting a limitation of this cannabis constituent. We also found CBGA to affect many epilepsy-relevant drug targets.”

Using a signaling assay to screen the pharmacological actions of CBGA at various different receptors, the researchers determined that the cannabinoid demonstrates some activity at numerous epilepsy-relevant targets, namely the GPR55 receptor, TRPV1 channels and GABAA receptors.

The researchers also noted that, when applied in conjunction with clobazam, a traditional anti-epilepsy drug, the resultant elevation in seizure threshold temperature was greater than when either drug was applied alone. Similarly, combination clobazam and CBGA was effective at reducing the frequency of spontaneous seizures and generalized tonic-clonic type seizures.

An interesting pharmacokinetic interaction was also observed, where the use of clobazam and in conjunction with CBGA significantly increased the plasma concentration of CBGA seen during treatment. This may explain the synergy between clobazam and CBGA that resulted in the higher onset temperatures for thermally-induced seizures, the researchers suggest.

About the Lambert Initiative

This new research was led by researchers from the Lambert Initiative for Cannabinoid Therapeutics, a research initiative established at the University of Sydney following a multi-million dollar donation from Barry and Joy Lambert in 2015. The Lambert family’s granddaughter Katelyn has Dravet syndrome and found relief through using a cannabis extract.

“After using hemp oil for treatment, we got our daughter back,” said Michael Lambert, Katelyn’s father, in a statement. “Instead of fearing constant seizures we had some hope that our daughter could have a life worth living. It was like the noise cleared from her mind and she was able to wake up. Today Katelyn really enjoys her life.”

Through the Lambert Initiative, the Lambert family’s donation now funds research into understanding how these cannabis extracts work to treat epilepsy and other health conditions.

“We have assessed the cannabinoids one by one and now we are exploring what happens when you put them all back together. There remains a real possibility that all these individual anticonvulsant cannabinoids might work better when combined,” Dr Anderson said.

Barry Lambert said: “We are very proud of the work done by the many researchers at the Lambert Initiative, which is a world-leader in cannabinoid research, and in particular welcome these recent results on ‘the mother of all cannabinoids’.”


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