Hashing Out Clinical Cannabis Research with the Society for Neuroscience

Michigan Pushes to Protect Medical Marijuana Dispensaries
Photo by Matthew Staver/For The Washington Post via Getty Images

With over 30,000 neuroscientists in attendance, the Society for Neuroscience Annual Meeting is the largest source of contemporary brain research in the world. This year’s conference in San Diego, held last month, featured talks and posters from scientists across the research spectrum.

I’ve previously described the hurdles scientists face in legally researching cannabis. One of these hurdles is the need to provide strong justification for possessing the DEA Schedule I license to study cannabis and its derivatives (e.g., cannabidiol). And despite the growing acceptance of medicinal cannabis, its Schedule I classification, by definition, essentially negates its therapeutic potential in the eyes of the funding agencies that largely dictate the direction of research (much of the funding to study the medicinal benefits of cannabis come from private foundations).

Therefore, the majority of research presentations involving THC was focused on public health-related questions, such as how perinatal or adolescent exposure affected brain development and behavior. I’m rarely surprised when studies reveal that artificially manipulating a developing brain with drugs, stress or trauma has harmful consequences. It’s best if kids don’t chug Red Bulls, live in an abusive home or play football. While the harmful effects of THC on the developing brain are now better understood than ever, it remains unclear whether high CBD strains have a protective effect against THC’s effects.

Still, mounting evidence for the benefits of clinical cannabis can’t be ignored.

Scientists with and without Schedule I research licenses are seeking to gain an improved understanding of the brain’s endogenous cannabinoid system to better understand how cannabis or other drugs may work to provide clinical benefits. It’s long been accepted that the CB1 receptor is the primary receptor on brain neurons that mediate the effect of endogenous cannabinoids, such as 2-AG, and exogenous cannabinoids, such as THC.

However, recent evidence has pointed to an important contribution of the CB2 receptor, despite making up less than 1 percent of the brain’s cannabinoid receptors. A research group from the Barrow Neurological Institute in Phoenix investigated the role of CB2 receptors in the brain area involved with learning and memory called the hippocampus. They found that CB2 activation increased the strength of the signaling rhythms within the hippocampus while rats completed a maze. In addition to revealing a significant CB2 role in spatial learning, this finding has important implications for disease states as signaling deficits in the hippocampus are associated with depression and anxiety. Whether CB2 activation in the hippocampus could act as an antidepressant or anxiolytic is an enticing hypothesis that remains to be tested.

The CB1 receptor has also gained attention as a therapeutic target, and it’s becoming increasingly accepted that cannabis can be an effective treatment for chronic pain. There are also a number of reports suggesting that cannabis substitutes for opioid-based medications such as OxyCotin and morphine.

THC is known to enhance morphine’s pain-relieving effects, enabling smaller doses of opiates to achieve the desired effect. Indeed, there are fewer opioid overdoses in states with legal medicinal cannabis. However, the neural mechanisms underlying these effects are not well-understood.

Research presented from the Levi Lab out of Mount Sinai in New York provided hints to the mechanism underlying cannabis’ efficacy at treating chronic pain. They induced chronic pain in rats by repeated injections of the chemotherapy drug, Paclitaxel. They then measured the distribution of CB1 receptors and the delta-opioid receptor, of which activation has been shown to dampen chronic pain. The researchers focused on receptor expression levels in an area called the dorsal root ganglia, which serves as a gate for incoming pain signals to the spinal cord and up to the brain where pain is consciously perceived.

Therefore, blocking incoming pain signals at the level of the dorsal root ganglia is a common pain relieving strategy. They presented evidence that CB1 receptors and delta-opioid receptors form a single unit in the dorsal root ganglia, and their expression increased by 200 percent after induction of chronic pain from chemotherapy treatment. The researchers found that neither activating CB1 receptors alone, nor delta-opioid receptors alone, relieved pain, but a drug cocktail that activated both CB1 and delta-opioid receptors was a highly effective pain relieving strategy. So with chronic pain, cannabis may decrease the minimum amount of opioid medication needed for pain relief by synergistically acting to block incoming pain signals into the spinal cord.

However, one of the challenges of treating pain with THC-rich cannabis is that repeated THC exposure reduces the number of available CB1 receptors. This limits the long-term efficacy of this treatment strategy because signaling between neurons requires two main components, neurotransmitters and their receptors, and a decrease in either component can reduce the strength of communication.

Activation of CB1 receptors, by THC for example, leads to a reduction in the number of CB1 receptors available to detect either endogenous cannabinoid neurotransmitters or exogenous cannabinoids like THC. This leads to a weakened effect (also known as “tolerance”, where an increasing amount of drug is needed to achieve a desired effect). In the case of pain treatment, reduced CB1 expression is problematic because pain treatments that target the cannabinoid system, and possibly the opioid system, are less effective. One strategy is to optimize the ratio of THC:CBD in medicinal cannabis to minimize CB1 receptor reduction. Another is to develop a selective CB1 receptor agonist that can activate CB1 receptors without causing them to be removed from their position on the neuron for detecting neurotransmitters, known as “the synapse”. Researchers from the University of Arkansas presented their new synthetic CB1 receptor agonists (i.e., drugs that activate the receptor) that resist the development of drug tolerance. These drugs can activate CB1 receptors without allowing the receptors to recruit the cellular machinery that leads to their removal from the synapse. This has great potential utility in future pain medications that target the cannabinoid system.

CB1 and CB2 receptors aren’t cannabis’ only therapeutic targets, and it’s widely accepted that the medicinal benefits of CBD largely stem from action on a different neurological target. For instance, CBD retains its medicinal benefit in genetic mice strains lacking CB1 or CB2 receptors. So it’s unclear what brain targets are mediating CBD’s effects, but perhaps there will soon be an accepted CB3 receptor.

A couple of research groups were in San Diego to shed light on this issue, and we were one of them. The two primary aims of our research were to first characterize CBD’s efficacy in treating seizures and social deficits caused by genetic mutation, and second, identify CBD’s neuronal target. We presented our latest findings—no, I wasn’t just attending the conference to escape the Seattle rain—demonstrating that CBD reduced seizures and improved autistic-like social impairments in our pre-clinical model of Dravet Syndrome.

We also revealed that CBD’s ability to treat symptoms of Dravet Syndrome likely stems from its inhibition of a receptor known as GPR55 (which stands for G-Protein-coupled Receptor 55). In support of these findings, a group from New York University presented similar evidence that CBD inhibited GPR55 action and protected against drug-induced seizures in rats. Their detailed description of the molecular consequences of CBD inhibition of GPR55 signaling provides valuable insight into the neural signature of CBD’s medicinal benefit. Together, our research provides needed pre-clinical evidence of CBD’s efficacy in treating seizures and adds further support for making GPR55 the once-elusive CB3 receptor.

Since November 7, many scientists have been fearing orange, and representatives from the Canadian Association for Neuroscience reported heightened interest from American scientists. But for those of us researching green, the spread of legalization across the U.S. demands a better understanding of cannabis’ clinical benefits.

The medical establishment’s stance against medicinal cannabis is softening, a trend that will continue as we better understand how to unlock cannabis’ medicinal potential in the safest, most efficacious and long-lasting manner. And if those in power try to limit us, we’ll take our case straight to them. After all, next year’s meeting is in DC.

For all HIGH TIMES’ medical marijuana coverage, click here.

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