Parsing the Contradictions: Marijuana and the Brain

California’s Proposition 64, or the Adult Use of Marijuana Act, passed on Nov. 8, 2016, making it legal for people 21 and older in that state to use marijuana recreationally. California is just the latest—more than 20 states have now legalized some manner of Cannabis sativa use and it is expected that more will follow. At Neuroscience 2016, the annual meeting of the Society for Neuroscience, Nora Volkow, director of the National Institute of Drug Abuse, said these changes in legislation are cause for concern.

“With the changes in legislation, we are already seeing an increase in consumption of marijuana across the population of the United States,” said Volkow, also a member of the Dana Alliance for Brain Initiatives. “Of particular concern for us is what are the effects on the developing brain? Because new research is showing that there can be adverse effects of both fetal and adolescent exposure to tetrahydrocannabinol (THC), one of the active ingredients of marijuana. But, on the other side of the coin, other research is showing that marijuana’s components may also have therapeutic potential. This is research that has really been neglected—and that needs to change, because with increase in usage, neuroscience can offer us information about how to prevent the negative effects of marijuana but, at the same time, tell us how we can take advantage of the drug, and the brain circuits it affects, for treatments for pain and other diseases.”

Neuroscientific research into marijuana use is largely a bundle of contradictions. The plant engages the brain’s natural cannabinoid system, a network of receptors that bind with both neurotransmitters and THC that is involved in the regulation of a variety of central and peripheral nervous system functions.

“This is a really important system,” said Andrea Hohmann, a neuroscientist from Indiana University. “It consists of cannabinoid receptors that can engage the constituents of marijuana, like THC and cannabidiol (CBD), and then have specific enzymes that control the synthesis and metabolic breakdown of those constituents and then release the brain’s natural THC-like chemicals called endocannabinoids that can then act on neurotransmitters.

“The activation of the cannabinoid pathways in the brain have many desirable therapeutic properties and can help with pain and other issues,” she said at the meeting. “But the problem is that engaging these receptors using marijuana also produces unwanted psychoactive side effects like the marijuana high.”

How do we harness the brain’s endocannabinoid system for therapeutic effect without engaging those undesirable side effects? It’s an open question—and studies at Neuroscience 2016 suggest that we need more research, with an increased focus on how the drug influences the brain at the epigenetic, cellular, and behavioral levels, to better parse this drug’s many contradictions.

Detrimental to development

Yasmin Hurd, a neurobiologist at the Mount Sinai Medical School, has been studying the epigenetic effects of marijuana use for years. She says that the reason why many have not studied marijuana in the past is because it was believed pot simply wasn’t addictive—and it did not have the same kind of mortality rates cocaine and heroin do.

“We are learning, however, that marijuana is not as benign as people thought,” she said. “And you actually see more people in the US who are clinically dependent on marijuana than on drugs like heroin or cocaine. A lot more people are using it, especially young people. So it’s important to study what impact it could have on the developing brain.”

That impact appears to be significant. In a talk entitled, “Translational Neuroepigenetic Insights of Addiction Vulnerability,” Hurd discussed how her research is demonstrating that both adolescent marijuana use, as well as exposure to THC in utero, makes epigenetic changes to the brain, priming it for greater susceptibility for later addiction to opiate drugs.

“We see specific morphological changes in the brain to important neurotransmitter systems, and individuals who are exposed to THC early in life show greater sensitivity to opiates than others do,” she said. “We know that the brain definitely adapts to marijuana. It is profoundly changing the receptors and receptor signaling that impact gene expression. And the changes it makes last through adulthood and even into the next generation. So we see that there’s something about the ongoing processes in the developing brain that this drug somehow sensitizes—in the cells, the receptors, and in the signaling cascades—that makes kids more vulnerable to addiction and other problems later.”

Taking advantage of the circuitry

But, as Volkow also noted, the endocannabinoid system also holds great promise for medical treatment—especially as a potential replacement for the highly addictive opioid and opiate medications used to treat pain. Haney said that researchers are both looking at different compounds in marijuana, like THC and CBD, as treatments for ailments ranging from migraines to epilepsy. They also are looking to better understand the brain’s cannabinoid system so they can perhaps activate different therapeutic pathways without the need of Cannabis sativa itself.

Several researchers presented studies at Neuroscience 2016 suggesting how these two approaches might make for successful treatments in the future. Hohmann found that a specific endocannabinoid receptor, CB1, may offer the potential for new neuropathic pain treatments without the psychoactive side effects commonly found with marijuana use. Researchers with Abide, a pharmaceutical company, presented data on how blocking a specific protein, MGLL, results in increased endocannabinoid release and reduction of pain in animal models. Sabrina Lisboa, a researcher from the University of Sao Paolo Medical School, discussed how a synthetic cannabinoid reduced anxiety and inflammation in a mouse model of post-traumatic stress disorder. Maria Garcia-Gutierrez, a researcher from Miguel Hernandez University in Spain, said that marijuana’s CBD may aid in treating alcoholism. And Hurd’s laboratory is looking at CBD as a potential treatment for anxiety and craving in drug addicts.

Haney said that our scientific understanding of marijuana’s effects on the brain is still in its infancy. But as we learn more about the cannabinoid system and how we might modulate its receptors for therapeutic use there is quite a bit of promise.

“These pre-clinical studies show us that it is possible to enhance or augment the brain’s existing physiology with this natural cannabinoid system to help with pain and other conditions,” she said. “We know that opiates and opioids don’t work as well as we hoped, and they are very addictive. These studies offer the possibility that there are other ways to treat pain without all the negative side effects.”

Moving forward

While some see great potential in marijuana as a therapy for a variety of ailments, others worry about the long-term effects of its increased use, medically or recreationally. But Haney says, no matter where you may stand on medical marijuana, everyone agrees that more research is necessary.

“Society has moved ahead. They are already using marijuana for all manner of ailments, from pain to headaches,” she said. “It’s frustrating to see society move ahead with little to no input from the scientific community. There is a lot of possibility here. But we haven’t done the work yet. We really have quite a bit of catch-up to do.”

Hurd agreed. “There may be therapeutic purposes for marijuana. But I don’t know of any drug that doesn’t have side effects,” she said. “There is a lot of optimism for what components of the marijuana plant may offer on a medicinal level but, like all other drugs, the caveat is that you have to know what it does, what population it can be used for, and who could be vulnerable to its effects. We need a lot more research before we can say anything concrete about its future as a treatment.”