CBD's Effect on Aggressive Mice Offers Glimpse of Its Powerful Potential

"It is amazing to see how this work is being spread." 

These days, it’s easy to get Mad Online or just frustrated in real life. It’s ideal for the CBD industry, which is hoping that its products can help an entire generation of millennials find a little more chill. Scientists are also probing CBD’s effect on mood and turning up some intriguing results, like the discovery that it can reduce aggression in mice, outlined in a Progress in Neuro-Psychopharmacology and Biological Psychiatry study published in May.

CBD, short for cannabidiol, is a molecule extracted from cannabis that can’t get you high but has other effects that have drawn interest from researchers in a variety of medical fields, including epilepsy treatment and psychology. In the paper published in May, a team of scientists from Brazil showed that CBD can help subdue aggression in mice via serotonin receptors as well as the endocannabinoid system. The compound’s effect on the latter is already well known.

These results may appear to hint at an explanation for CBD’s chill reputation. But corresponding author Sabrina Lisboa, Ph.D., a post-doc at the University of São Paulo’s Ribeirão Preto Medical School, tells Inverse that they bolster the idea that CBD might have potential as an anxiolytic (a treatment for anxiety) or as an anti-depressant.

“Aggression is not a mental disease per se, but is a trait frequently observed in mental illness, such as schizophrenia, anxiety disorders, PTSD, autism spectrum disorder,” Lisboa says. “There are already several clinical trials going on with CBD in patients with depression, schizophrenia and autism, for example, all showing very promising results.”

CBD isn’t a substitute for approved treatments for these conditions. For now, Lisboa is simply intrigued by its future medical potential.

Hemp
CBD helped reduce aggressive behavior in mice. 

CBD and Aggression

The study focused on mice that had experienced fairly bleak circumstances. First, they were isolated for ten days, leading them to become aggressive and attack others once they’re re-socialized.

To evaluate the effects of CBD, Lisboa and her team gave one group of the aggressive mice CBD injections ranging from five to 60 mg/kg of body weight. Then, these angry mice went through the “resident intruder test.” In this test, scientists introduced angry mice to a new friend, then waited to see whether CBD impacted the way these isolated mice lashed out.

Overall, mice that received any amount of CBD attacked the “intruders” less than the mice who didn’t get any CBD, and mice that got intermediate doses of 15 to 30 mg/kg spent less time attacking the intruders than controls.

But in both groups, mice were equally eager to take the first bite of the intruder. CBD made no difference in how long it took the mice to start their attacks.

The authors concluded that their results demonstrated a connection between CBD and reduced aggression. When they probed their results in detail, they discovered CBD-related biochemical changes that may explain what they saw.

marijuana, cannabis
CBD, the non-psychoactive component in cannabis is being looked into for a variety of medical conditions. 

They observed that CBD activated two kinds of receptors in their mice. One was the 5-HT1A receptor, implicated in the control of mood because it binds with serotonin (low serotonin levels are one of many factors that underlie clinical depression). The CB1 receptor, meanwhile, is part of the body’s endocannabinoid system — a network of neurotransmitters and receptors that Lisboa describes as “a buffer system” that can modulate stress responses.

“Aggression could involve disturbances in serotonin and endocannabinoid mechanisms and CBD could attenuate this by promoting a regulation of these systems,” Lisboa proposes. “We don’t know how CB1 and 5-HT1A receptors act to attenuate aggression though.”

A Good Start, but a Long Way to Go

While the team in Brazil is enthusiastic about CBD’s potential for medicine, there are still lots of reasons that this connection needs to looked at in far more detail.

From the FDA’s perspective, CBD’s regulatory landscape in the US is inconsistent. CBD is readily sold on shelves and marketed as a way to be more chill, but sometimes those claims go a bit too far. Making certain health-based claims about the CBD can lead to warnings from the FDA.

On July 22, the agency slapped Curaleaf Inc., a cannabis “wellness operator” in Wakefield, Massachusetts, with a warning letter. According to the letter, the company received FDA attention because it sold unapproved CBD products that made unsubstantiated claims, including a tweet on March 25 claiming that “CBD is being adopted more and more as a natural alternative to pharmaceutical-grade treatments for depression and anxiety.”

These claims are concerning because CBD isn’t a substitute for medically verified treatment of mood disorders.

That doesn’t mean that it’s not worth investigating what potential CBD might have in the future. Some of those human clinical trials are happening right now. For example, one clinical trial in Brazil is currently examining the effects on CBD on humans with bipolar depression.

For now, Lisboa’s paper, alongside other ongoing trials, is a good start. But there’s still a long way to go, no matter how fast the CBD industry is moving. Lisboa, for one, is hopeful that we’ll get answers soon.

“It is amazing to see how this work is being spread,” she adds. “That’s really exciting!”

Abstract:

Long-term single housing increases aggressive behavior in mice, a condition named isolation-induced aggression or territorial aggression, which can be attenuated by anxiolytic, antidepressant, and antipsychotic drugs. Preclinical and clinical findings indicate that cannabidiol (CBD), a non-psychotomimetic compound from Cannabis sativa, has anxiolytic, antidepressant, and antipsychotic properties. Few studies, however, have investigated the effects of CBD on aggressive behaviors. Here, we investigated whether CBD (5, 15, 30, and 60 mg/kg; i.p.) could attenuate social isolation-induced aggressive behavior in the resident-intruder test. Male Swiss mice (7–8 weeks) were single-housed for 10 days (resident mice) to induce aggressive behaviors, while conspecific mice of same sex and age (intruder mice) were group-housed. During the test, the intruder was placed into the resident’s home-cage and aggressive behaviors initiated by the resident, including the latency for the first attack, number of attacks, and total duration of aggressive encounters, were recorded. The involvement of 5-HT1A and CB1 receptors (CB1R) in the effects of CBD was also investigated. All tested CBD doses induced anti-aggressive effects, indicated by a decrease in the number of attacks. CBD, at intermediary doses (15 and 30 mg/kg), also increased latency to attack the intruder and decreased the duration of aggressive encounters. No CBD dose interfered with locomotor behavior. CBD anti-aggressive effects were attenuated by the 5-HT1A receptor antagonist WAY100635 (0.3 mg/kg) and the CB1 antagonist AM251 (1 mg/kg), suggesting that CBD decreases social isolation-induced aggressive behaviors through a mechanism associated with the activation of 5-HT1A and CB1 receptors. Also, CBD decreased c-Fos protein expression, a neuronal activity marker, in the lateral periaqueductal gray (lPAG) in social-isolated mice exposed to the resident-intruder test, indicating a potential involvement of this brain region in the drug effects. Taken together, our findings suggest that CBD may be therapeutically useful to treat aggressive behaviors that are usually associated with psychiatric disorders.