The Other Cannabinoids: CBD and CBDV

Cannabidiol (CBD)

Much ink has been spilled on proving the beneficial properties of cannabidiol. It’s anxiolytic, antidepressant, antipsychotic, anticonvulsant, anti-nausea, antioxidant, anti-inflammatory, anti-arthritic and antineoplastic (anti-tumor), and its efficacy against the diseases of aging is powerful and unparalleled. But the mystery still remains for the pharmacologists to ponder: How the hell does CBD work?

CBD barely binds to the best known cannabinoid receptors—the CB1 receptors, which are spread across the brain, and the CB2 receptors within most of the organs. Even its relationship to THC and how the presence of CBD affects the psychoactivity and other properties of THC is still not settled definitively, but it does seem to potentiate THC in a number of ways.

CBD acts as an antagonist at GPR55—the “putative” (commonly assumed) CB3 receptor. It also binds at several of the transient receptor potential (TRP) channels, sites in the cell wall that mediate sensations like pain or pressure by allowing electrical ions through the membrane.

Researcher Vincenzo Di Marzo characterized them as “ionotropic cannabinoid receptors” for the ability of the cannabinoids to regulate the transmission of sensations. CBD also stimulates adenosine receptor (the ones antagonized by caffeine) signaling, and this may account for its help for arthritis and other pain conditions.

Intriguing results show that CBD interacts with the 5-HT1A partial agonist serotonin receptor, which might underlie its strong antianxiety effects and noted antidepressant actions. For pain, it acts as an allosteric modulator of some of our opioid receptors; some evidence suggests that CBD changes the binding properties of the opioids. For patients, this can mean that they can decrease their use of addictive painkillers. Similar allosteric modulations occur at the dopamine receptor D2, activated by stimulants, and the GABAa receptor, activated by alcohol, barbituates and GHB.

Deeper still, CBD binds to the PPAR-γ receptors that live on the membrane of the nucleus of certain cell. An Israeli study found 680 genes upregulated and 524 downregulated by CBD, a downstream effect so wide that it’s hard to imagine ever truly plumbing its depths.

The ability of CBD to lessen acute and chronic inflammation is one of the sexiest of its properties. CBD decreases the production of nitric oxide—a signaling molecule so vital to cellular communication that it was named “Molecule of the Year” in 1992. In addition, a dozen studies have shown CBD can inhibit the expression of inflammatory cytokines and transcription factors.

CBD is especially potent as an antioxidant. It reduces the production of reactive oxygen species (ROS) in healthy cells, but increases the levels in cancerous tissue, leading to their suicidal apoptosis.

Of all of CBD’s effects, the inhibition of the fatty acid amide hydrolase (FAAH) might matter most. This enzyme, a molecular network of the endocannabinoid system, is responsible for breaking down anandamide—the first discovered endogenous cannabinoid, a major a neurotransmitter swimming around the depths of our brain. With CBD inhibiting the FAAH enzyme, the levels of our own natural cannabinoid anandamide rise.

With this host of biochemical effects, it’s no wonder that CBD shows such strong medical benefits and potential, but figuring out the biochemical details will keep researchers fitting together new pieces and making discoveries for decades to come.

Cannabidivarin (CBDV)

While the pharmacological data on CBD alone is overwhelming, the information on its understudied cousin, the varin form of CBD—known as CBDV—can be reviewed much more rapidly despite the clear benefit for many medical conditions.

Since the non-intoxicating CBD showed the most promise for epileptic children who risk starving to death due to their hundreds of daily seizures, scientists naturally looked to its propyl analogue: cannabidivarin, originally discovered in 1969. It took more than 40 years for the compound to first be studied in animals. In 2012, anticonvulsant effects on two in-vitro models and four rodent models of epilepsy were demonstrated, while also showing compatibility with the existing meds for the condition and no negative effects on motor control.

Follow-up research in 2013 looked at extracts from the whole plant; they experimented with leaving in the THC and found the only negative to be the effect on motor control. It’s not so much that the animals couldn’t control their bodies, as much as—perhaps somewhat predictably—they tended to stay in one place and not bother walking the balance beam as trained.

CBDV’s mechanism of action is still unknown, though it might be activation of the TRPV1 channels that are expressed in the brain.

Tetrahydrocannabivarin (THCV) received initial interest from GW Pharmaceuticals, but the activation of CB1 receptors, made CBDV even more attractive to the British company. By 2014, their Phase 1 study treated 66 healthy subjects with no reported adverse effects. Their Phase 2 study began last spring with CBDV—now designated GWP42006—as an add-on medication for “inadequately controlled focal seizures.” Around the same time, they were awarded a U.S. patent for the treatment of general or temporal lobe seizures with Epidolex, their liquid formulation of CBD for convulsion control.

We get the benefits of all the cannabinoids, working together, with whole plant cannabis. But isolating these individual cannabinoids has become increasingly appealing for pharmaceutical applications.

Lex Pelger is a writer and scientist, and hosts the Psymposia drug conference and “Psychoactive Storytelling” events.

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