National health regulators in several nations approved a pharmaceutical CBD-dominant cannabis formulation for the relief of Dravet Syndrome. Historic medical records, some dating back several hundred years in age, document the use of cannabis extracts as a seizure remedy. Despite centuries of scientific documentation, though, we do not know why CBD, CBDv, or other ingredients like linalool treat epilepsy and seizure related illnesses.
Cannabis, a plant in the Cannabacae family, contains numerous therapeutic ingredients. Cannabinoids and terpenes are abundant constituents providing a wealth of biological activity. Cannabidiol (CBD), for example, is a dominant cannabinoid in Type III cannabis chemovars, which is a system broken down by chemical composition.
Patients find out what terpenes to avoid through a trial-and-error process that proves cumbersome even with educators and second-hand experience. Moreover, a lack of an identified mechanism limits educational tools to anecdotal reports. Knowledge of how CBD can relieve seizures caused by Dravet Syndrome or Lennox-Gastaut Syndrome helps patients and clinicians find more effective chemovars.
Cannabidiol (CBD) especially binds to various receptors, enzymes, and channels. But many papers blame one mechanism for epilepsy-related illnesses while narrowing down the cannabinoid’s polypharmacy. The theory suggests that CBD relies on deactivating a receptor known as GPR55 to treat epilepsy and seizure related illnesses.
Finding a target for CBD and epilepsy
Eliminating any of CBD’s many targets helps narrow down the list. Researchers use lab mice to achieve an initial conclusion. Essentially, we can blame the receptor if mice engineered with a GPR55 deletion develop absolute seizure resistance. And they can further breed mice with an epileptic phenotype to ensure a result.
A study published in PLOS One, engineered mice with a loss of function typical of Dravet Syndrome, which leads to thermal seizure susceptibility. The lost mechanism was a sodium ion current (NaV1.1), but some mice without the ion current displayed seizure resistance. It’s implied that an adjacent gained or lost function prevents seizures in the phenotype. (1)
Researchers from the University of Sydney bred mice with their genetic code for GPR55 receptors snipped from one parent using CRISPR technology. The breeding method they used, cutting genes from one parent, is called a heterozygous deletion. But studies have yet to discuss the complete elimination of code for GPR55, which is rather known as a homozygous deletion. And the hetero GPR55 deletion did not stop temperature-induced seizures.
GPR55 inhibitor deficits
It has been postulated that the receptor has major roles in epilepsy-related conditions. Previous results indicate that current GPR55 inhibitors stop Dravet's symptoms with similar efficiency as CBD. Research to prove or disprove the idea that treatment depends on blocking the receptor is not without problems, though.
Alongside genetically shutting down a receptor, pharmaceutical inhibition can also uncover a wealth of data about its function during disease. The team chemically shut down mouse GPR55 receptors testing their role in epilepsy-related Syndromes. Unfortunately, though, synthetic GPR55 antagonists are not selective. And a lack of a method capable of replicating results bodes well for CBD’s elusive status.
Cross-talk with cannabinoid receptors
GPR55 initially dawned the name — the purported Cannabinoid 3 Receptor — due to its involvement with CBD, THC, and several endocannabinoids. More recent discoveries confirmed that a different fatty acid ligand known as LPI instead binds GPR55. But this G-protein coupled receptor does, however, bind to (2) and negatively interact with CB2 receptors. (3)
GPR55 deactivation should, in turn, pick up CB2 receptor activity. And the same is true in reverse for CB2 receptor agonists; a function called negative crosstalk. It turns out that CBD agonizes CB2 receptors and deactivates GPR55. Essentially, the cannabinoid may depend on either end of the complex to treat seizures. This means that their mouse model was further incomplete due to a lack of CB2 receptor elimination. And CBD desensitizes TRPV1, an ion-regulating channel, which may act as a third pillar of therapy for a neurological condition related to an ion current function.
Currently, models cannot yet identify the target CBD acts on to treat epilepsy, or thermal-induced seizures related to Dravet Syndrome, for example. Although, the latest research indicates that CBD does not depend on GPR55 receptor deactivation alone, despite previous results. For now, we have historic texts, anecdotal reports, and nationally recognized, placebo-controlled, double-blind Phase III trials to validate the use of CBD for seizures and their related illnesses.
Sources
1. Anderson LL, Bahceci DA, Hawkins NA, et al. Heterozygous deletion of Gpr55 does not affect a hyperthermia-induced seizure, spontaneous seizures or survival in the Scn1a+/- mouse model of Dravet syndrome. PLoS One. 2023;18(1):e0280842. Published 2023 Jan 26. doi:10.1371/journal.pone.0280842
2. Balenga NA, Martínez-Pinilla E, Kargl J, et al. Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling. Br J Pharmacol. 2014;171(23):5387-5406. doi:10.1111/bph.12850
3. Balenga NA, Aflaki E, Kargl J, et al. GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils [published correction appears in Cell Res. 2011 Nov;21(11):1641]. Cell Res. 2011;21(10):1452-1469. doi:10.1038/cr.2011.60
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