With widespread legal approval of marijuana growing, scientific research into some of the more elusive details of this drug can be explored. For instance, it has been previously shown that strains of cannabis with high levels of tetrahydrocannabinol (THC) and low levels of cannabidiol (CBD) can cause increased psychiatric effects, including paranoia, anxiety, and addictive-behaviors. Yet, why this occurs had been a mystery until now, as investigators from the University of Western Ontario, recently showed for the first time the molecular mechanisms at work that cause CBD to block the psychiatric side-effects caused by THC.

“For years we have known that strains of cannabis high in THC and low in CBD were more likely to cause psychiatric side-effects,” explained senior study investigator Steven Laviolette, PhD, a professor at Western’s Schulich School of Medicine & Dentistry. “Our findings identify for the first time the molecular mechanisms by which CBD may actually block these THC-related side-effects.”

The research team used rats to investigate the role of a molecule in the brain’s hippocampus called extracellular-signal-regulated kinase (ERK), which triggers the neuropsychiatric effects of THC. The group published their findings recently in the Journal of Neuroscience through an article titled “Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus Through Bi-Directional Control of ERK1-2 Phosphorylation.”

In the study, the researchers saw that rats given THC had higher levels of activated ERK showed more anxiety behaviors and were more sensitive to fear-based learning. Rats that were given both CBD and THC acted like the control rats: they had normal levels of activated ERK, fewer anxiety behaviors, and were less sensitive to fear-based learning.

“Using in vivo electrophysiology in male Sprague Dawley rats, we demonstrated that intra-vHipp THC strongly increases ventral tegmental area (VTA) DA neuronal frequency and bursting rates, decreases GABA frequency, and amplifies VTA beta, gamma, and epsilon oscillatory magnitudes via modulation of local extracellular signal-regulated kinase phosphorylation (pERK1-2),” the authors wrote. “Remarkably, whereas intra-vHipp THC also potentiates salience attribution in morphine place-preference and fear conditioning assays, CBD co-administration reverses these changes by down-regulating pERK1-2 signaling, as pharmacological re-activation of pERK1-2 blocked the inhibitory properties of CBD.”

Based on these results, the research team proposes that CBD blocks the ability of THC to overstimulate the ERK pathway in the hippocampus and thus prevent its negative side-effects.

“Our findings have important implications for prescribing cannabis and long-term cannabis use. For example, for individuals more prone to cannabis-related side-effects, it is critical to limit use to strains with high CBD and low THC content,” said Laviolette. “More importantly, this discovery opens up a new molecular frontier for developing more effective and safer THC formulations.”

Amazingly, the researchers also found that CBD alone had no effect on the ERK pathway. “CBD by itself had no effect,” noted lead study author Roger Hudson, a PhD candidate at the University of Western Ontario. “However, by co-administering CBD and THC, we completely reversed the direction of the change on a molecular level. CBD was also able to reverse the anxiety-like behavior and addictive-like behavior caused by the THC.”

Laviolette says they will be following up these studies by continuing to identify the specific features of this molecular mechanism. The research team will examine ways to formulate THC with fewer side effects and to improve the efficacy of CBD-derived therapies.

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