We recently talked about the complex process of ion currents and how they function in the body. Negatively charged endocannabinoids regulate a receptor in the heart that controls a vital potassium current. But like many researchers, clinicians, and journalists — I often overlook sodium channels, which induce electrical activity during epilepsy and pain.
Scrolling through Professor Codi Peterson’s LinkedIn posts will reveal my surprise at a link between cannabinoids and the ever-so-important sodium current. This author was quickly reminded of a unique trick played by TRP (transient receptor potential) channels. These are special transport machines, TRP-Vallinoid 1 for CBD and Ankryin 1 for THC, that move calcium and sodium ions through the cellular space in response to heat or chemical exposure.
It turns out that cannabis ingredients also bind directly to special sodium channels. A new study published in Frontiers of Physiology looked at rare phytocannabinoids in cannabis. Researchers from the Universities of Sydney and Melbourne tested CBGa, CBDVa, CBCa, and CBC on human kidney cells. As an ion, sodium communicates signals between the vital cells and neurons, which means that phytocannabinoids might calm electrical impulses in the brain. (Milligan et al. 2023)
Science leading up to CBG and CBC
Our understanding of phytocannabinoids dates back to the 1800s when two chemists found a constituent, oxy-cannabin, after exposing hashish to nitric acid. (Bolas & Francis, 1869) Before then, chemists managed to separate cannabis oils using chromatography and other methods. The active ingredient was first crudely extracted for scientific research in 1840, which was named “cannabin” in 1848 (Kogan & Mechoulam, 2007) And then, in 1896, three scientists identified an active cannabinoid — cannabinol (CBN).
It’s unlikely that Spivey, Wood, and Thomas Easterfield, Ph.D. elucidated CBN in 1896, though. Rather, according to a paper authored by Dr. Mark Scialdone, their analysis was a few hydrogen atoms shy. If that is true, then THC was first identified in the late 1800s. (Scialdone, 2021) But the precise analysis of THC was conducted decades later by Dr. Raphael Mechoulam and coincided with the elucidation of cannabigerol (CBG). (Gaoni & Mechoulam, 1964)
Cannabinoids identified
Dr. Raphael Mechoulam, working for Weizmann Institute in Israel with Yeihel Gaoni and Habib Edery, had access to nuclear magnetic resonance (NMR) and five kilograms of hashish from the local police station. The Journal of the American Chemical Society published his paper on the subsequent discovery, coauthored with Gaoni, in April 1964.
That was, conveniently, the same year that Roger Adams’ patent on cannabinoids expired. Adams identified CBD in 1942 using electron microscopy, which was two years after Robert Cahn formerly elucidated CBN. A decade later, Krejci and Santavy identified CBDa from cannabis in 1955, which was followed by Mechoulam and Gaoni’s discovery of CBGa in late 1964. The Israeli team then discovered cannabichromene two years later; a century after the discovery of oxy-cannabin. (Gaoni & Mechoulam, 1964. 1966.)
Cannabinoid research continues
Research on CBC and some of the rare cannabinoids is vague. But the latest discovery found that Cannabidivarinic acid (CBDVa) is selective to one channel known as Sodium Voltage gate Channel (Nav) 6.1. Whereas CBGa and CBD are far more promiscuous equals, binding to various channels. CBC and CBCa, on the other hand, are not remarkable ligands for any reported sodium currents.
Epilepsy is a symptom of various ailments, such as Dravet Syndrome. Different receptors, even closely related, play roles in unique epileptic subtypes. CBD and CBGa inhibit four voltage-gated sodium currents, including 1.1, 1.2, 1.6, and 1.7. Whereas CBDVa is more strongly selective to the 1.6 channel. (Milligan et al. 2023)
Earlier preclinical evidence suggests that CBDVa is promising for focal seizures. But isolated CBDVa failed a clinical trial for focal seizures, giving promise to whole plant formulations with specific terpenes and other cannabinoids. Yet, the latest discovery suggests that CBDVa provides a neuronal counterbalance in a sodium-defective mouse model of epilepsy.
CBD and CBGa for epilepsy
Electrical currents fire across the brain helping to maintain communication. Ions are atoms with the propensity to give away electrons, which means they are electrically active. Sodium is an example of an ion that becomes hyper-stimulated during pain or an epileptic attack. Phytocannabinoids that inhibit sodium currents, therefore, calm seizures and hypersensitivity.
CBD and CBGa might help with an acutely severe form of epilepsy that occurs during early infantile and childhood development. This is because they hyperpolarize the NAv1.1 channel, which inhibits its normal function. Otherwise, CBD and CBGa might reduce Lennox-Gastaut syndrome (LGS) severity in patients with a specific phenotype.
However, evidence suggests that CBGa also induces pro-convulsant activity, likely due to specific test parameters. And the latest research refutes previous conclusions suggesting that CBGa and CBDVa reduce thermally induced seizures in Dravet Syndrome.
Phytocannabinoids in the entourage
An enzyme in cannabis’s glands metabolizes CBGa into cannabichromene’s naturally occurring acidic precursor, CBCa. The latest discovery determined the CBC has low binding power at the tested sodium currents. But that doesn’t mean you should leave CBC out of the picture. Rather, this author considers the new study as evidence for CBC’s selectivity to CB2 receptor agonists, which can regulate the brain’s polarity under an inflammatory state. Moving downstream of CB2 receptor activity, cannabichromene, like THC, desensitizes the TRPA1 channel.
As research continues, we find not only new cannabinoids but the treasure cove of mechanisms they contain. CBGa and CBDVa might calm certain electrical activity during epilepsy or pain. Yet, the study was preclinical and only on human cells. But the latest discovery still opens a door to exciting discoveries with phytocannabinoids in human patients.
Let us know in the comments if you or someone you know relies on cannabinoids, such as CBGa or CBDva, to relieve excessive electrical activity in nerves or the brain for pain or epilepsy.
Authors note: The cannabis industry and scientific community recently shared their mutual respect in mass for Dr. Raphael Mechoulam after the 'Godfather of cCannabis Science' passed away in his home, at 92 years-old, early in the morning on March 10, 2023.
Show their work
Nv1.2 potentiates symptoms in LGS patients with SCN2A GOF mutations.
Nv1.6 inhibition assists with a neuronal counterbalance to the haploin sufficiency of the SCN1A model.
Nv1.1 worsens an extremely severe developmental and early infantile epileptic encephalopathy phenotype (B) expressing a GOF recurrent missense variant (p.Thr226Met) in the SCN1A gene.
NaV1.1 moves into an inactivated state as its normal function. And so hyperpolarization of the channel induced by CBD or CBGa inhibits the channel’s mechanism.
CBD or CBGa depolarizes Voltage-gated Sodium Ion Channel 1.7, which inhibits the channel’s mechanism.
CBC and CBCA produced anti-seizure mechanisms against hyperthermia-induced seizures in Scn1a+/− mice, independent of NaV channels.
Sources
Milligan CJ, Anderson LL, McGregor IS, Arnold JC, Petrou S. Beyond CBD: Inhibitory effects of lesser studied phytocannabinoids on human voltage-gated sodium channels. Front Physiol. 2023;14:1081186. Published 2023 Feb 20. doi:10.3389/fphys.2023.1081186
Bolas T, Francis EEH. XXXV.—On the products of the action of nitric acid on the resinous extract of Indian hemp. J Chem Soc. 1869;22(0):417-419.
Kogan NM, Mechoulam R. Cannabinoids in health and disease. Dialogues Clin Neurosci. 2007;9(4):413-430. doi:10.31887/DCNS.2007.9.4/nkogan
Wood TB, Spivey WTN, Easterfield TH. Xl. —charas. The resin of indian hemp. J Chem Soc, Trans. 1896;69(0):539-546.
Scialdone, M. Historical Perspective on Early Cannabinoid Isolation, American Journal of Endocannabinoid Medicine, Vol. 3, Issue 1, 2021, pp. 47-49
Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86(8):1646-1647.
R. Mechoulam; Y. Gaoni (1965). Hashish—IV: The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. , 21(5), 1223–1229. doi:10.1016/0040-4020(65)80064-3
Gaoni Y, Mechoulam R. Cannabichromene, a new active principle in hashish. Chem Commun (London). 1966;(1):20-21.