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  • Writer's pictureTom Clinton | Aificial Editor Chief

Neuroscientists make a warning about the use of cannabis

As states relax their laws on cannabis, neuroscientist Yasmin Hurd is warning about the drug’s dangers for the developing brain

Photo via: The Oklahoman
Photo via: The Oklahoman

One morning in June, barely 5 months after the first dispensary for recreational cannabis opened in New York state, neuroscientist Yasmin Hurd spoke via Zoom to an audience of educators and specialists who work with or run programs for children. The session’s organizers, alarmed by how many children in their South Bronx community were now getting their hands on cannabis, had sought Hurd’s expertise on the drug’s effects.


Hurd put up a slide of the human brain, its bumps and grooves tinged blue, green, yellow, and red to indicate the distribution of the receptors to which tetrahydrocannabinol (THC), the psychoactive ingredient in cannabis, binds. She showed how they exist throughout the brain—in the folds of the cerebral cortex, where much of cognition lies; the cauliflower-shaped cerebellum, the seat of motor coordination; the hippocampus, Grand Central for memory; and the amygdala, a crucial hub for emotional regulation.


The receptors, said Hurd, who heads an addiction research lab at the Icahn School of Medicine at Mount Sinai, are “really critical for so many processes in the brain.” And when a person uses cannabis—in any of its edible, dabbable, smokable forms—the drug overwhelms them and disrupts their ability to calibrate neuronal activity.


That, in turn, can be profoundly problematic for the developing brain, Hurd’s research suggests. She sees growing evidence in the field that cannabis use puts children and adolescents at risk for a variety of psychiatric problems, from dependence on that drug and others to schizophrenia. In utero exposure, she believes, can ignite mental health problems in childhood and beyond. In studies with rats, human fetal tissue, and children, her lab has begun to uncover changes in gene expression, as well as alterations in the brain’s chemical communication systems and wiring, that may underlie some of these effects.


Hurd’s work is especially compelling because she has been able to link results across species, colleagues say. “It’s so hard to be able to go back and forth between animal models and effects in humans,” says Susan Tapert, an addiction researcher at the University of California, San Diego. “She’s really one of the leaders in the field in being able to pull those very different kinds of studies together.” Tapert agrees the evidence for harmful effects on the developing brain are concerning, although she says the harm likely varies widely from one individual to another. The risks for adults are lower, she says, as the drug’s influences on memory, mood, sleep, and motivation tend to wane within about a month of discontinued use.

Research on cannabis’ developmental effects has grown in recent years, but Hurd “definitely pioneered this field,” says Miriam Melis, a neuroscientist at the University of Cagliari. Hurd also had to prove herself as a Black woman in a discipline then dominated by white men, Melis says. “For me she’s an inspiration of a woman in science.”


Her work has become increasingly relevant, as U.S. states—23 so far, plus Washington, D.C.—legalize cannabis for adult recreational use. Hurd’s findings raise “big red caution flags,” says Eric Nestler, an addiction researcher and director of the Friedman Brain Institute, which Hurd’s lab is a part of. Legalization is “not a free decision. It is a decision that, according Yasmin’s data—and I would agree with her data—will bring costs.”


Some adults might be able to use cannabis quite safely, experts say, yet the legalization trend has made the drug increasingly accessible to pregnant people and also children, who may ask adults to buy it, take it from parents, or use fake IDs to get it. In the Bronx, kids as young as age 11 or 12 know which shops will sell to minors, according to Davon Russell, president of the Women’s Housing and Economic Development Corporation, a Bronx community development organization, who invited Hurd to speak. At the same time, the potency of the products on offer has risen sharply (see graphic, below) and is only loosely regulated by states. Customers “have no clue about the substances they are consuming,” Hurd says. She has seen the consequences firsthand: Besides running her lab, she directs Mount Sinai’s Addiction Institute, overseeing inpatient and outpatient treatment centers, as well as programs for kids.


Although Hurd opposes the criminalization of cannabis use and possession, she believes legalization has come with underappreciated downsides. She’s concerned it has fanned a permissive culture and a perception that the drug is generally safe. “I am worried about how cavalier we’re becoming and that there is a cannabis smoke shop now practically, in some places, on every other block,” she says. “I feel frustrated that people are willing to sacrifice kids and young people for their quote-unquote right to get high.” Her science, she hopes, will foster a greater awareness of the potential harms.


HURD REMEMBERS HER FIRST science experiment.

At about age 6, she set up tin pans with rice outside her home in Jamaica, varying the amounts of water and shade to see how using sunlight to cook rice under differing conditions affected its quality. She was an inquisitive child who liked to question the rules. Why, she recalls asking her parents, did she have to drink milk? Did they know that humans are the only species that drinks other species’ milk?


Higher times

Cannabis plants, resins, and oils have gotten far more potent over the past quarter-century, according to an analysis of illegal samples seized by the U.S. Drug Enforcement Administration. Concentrations of tetrahydrocannabinol (THC), the main psychoactive ingredient, have risen as states have legalized cannabis use.


(GRAPHIC) D. AN-PHAM/SCIENCE; JULIA GREENWOOD/SCIENCE; (DATA) POTENCY MONITORING PROGRAM QUARTERLY REPORT #153, NATIONAL INSTITUTE ON DRUG ABUSE
(GRAPHIC) D. AN-PHAM/SCIENCE; JULIA GREENWOOD/SCIENCE; (DATA) POTENCY MONITORING PROGRAM QUARTERLY REPORT #153, NATIONAL INSTITUTE ON DRUG ABUSE

In the early 1970s, when Hurd was about 10, her parents divorced and she moved to New York City with her mother and siblings. She loved it from day one. “I’m definitely not a stereotypical Jamaican, in that some Jamaicans are just like, ‘No problem man, tomorrow, tomorrow.’ I came to New York, and everyone was moving, moving, moving,” she says, and thought: “This is my place!”


At South Shore High School in Brooklyn, she was the only Black person in her honors classes. “You are a Black girl and they are always challenging you that you really know anything,” she says. Yet she excelled in her science classes and studied German so she could read classic experiments in their original language. Hurd says her family valued education, and their high expectations helped propel her to college.


At Binghamton University, she convinced administrators to create a new degree for her: a B.A. in biochemistry and behavior. It was meant to blend her two main interests, chemistry and behavior—but she now jokes that it was essentially a neuroscience major before that became a thing. In graduate school at the Karolinska Institute in Stockholm, her colleagues gave her another lesson in expectations—this one not based on her skin color. “They said, ‘You’re American; therefore, you must be the best,’” Hurd says. Their high expectations motivated her to measure up.


In grad school, Hurd helped develop techniques for measuring neurotransmitters in the rat brain. In some of her experiments, she used amphetamine or cocaine to artificially raise dopamine levels. She was fascinated to see a mild-mannered rat suddenly become hyperactive, and at higher doses, aggressive and ready to pounce. “If you’ve never seen a paranoid rat,” she says, “it was just ferocious.”


As a postdoc at the National Institute of Mental Health in the early 1990s, she learned some of the then-new molecular biology tools to study how cocaine affected cells and receptors in rodent brains. But she wasn’t satisfied. “I needed it to have a human relevance,” Hurd recalls.

After finding a National Institutes of Health pathologist who had started a brain bank that included cocaine users, she set out to measure messenger RNA (mRNA) transcripts lingering in the tissue after death, hoping to gauge gene expression in the users’ brains. Other scientists told her she was on a fool’s errand because, they said, mRNA becomes unstable after death. But she proved them wrong, and was able to identify molecular changes in humans that matched findings in rats exposed to cocaine, as well as some key species differences in reward regions of the brain.


Neuroscientist Yasmin Hurd (bottom right) examines a slide of donated human brain tissue with students in her lab at the Icahn School of Medicine at Mount Sinai.DREW GURIAN
Neuroscientist Yasmin Hurd (bottom right) examines a slide of donated human brain tissue with students in her lab at the Icahn School of Medicine at Mount Sinai.DREW GURIAN

When Hurd returned to Karolinska as an assistant professor in the early 1990s, she set up her own brain bank, consisting primarily of users of amphetamine and heroin. “She was really a pioneer in using human brain tissue to understand the neurobiology of drug addiction,” Nestler says. Her brain collection, which she expanded at Mount Sinai, “provided assurance that mechanisms scientists study in the lab, say in rodent models, really focused on things that had human relevance.”

It was rodents alone, however, that enabled Hurd to make her first mark on the broader debate about cannabis. Epidemiological studies had suggested people who use cannabis early in life are more likely to later become addicted to drugs such as cocaine and heroin, inspiring the so-called gateway hypothesis. Many scientists and laypeople believed the effect was strictly environmental—that is, using cannabis is likely to introduce people to a drug-using crowd and to a dealer who also hawks harder drugs. But Hurd thought there might also be a biological connection. What if, she thought, cannabis changes the developing brain in a way that made some people vulnerable to addictive substances more generally?

To investigate, Hurd’s team exposed adolescent rats to THC and found the rodents later self-administered heroin at increasing rates, reaching dosages far higher than controls. Early THC exposure also altered gene expression in a reward center of the brain, they found, suggesting the drug can alter the brain’s endogenous opioid system, which is involved in the perception of reward, stress, and pain. Reviewers were skeptical, Hurd says, but the manuscript finally came out in 2007 in Neuropsychopharmacology, the year after she became a professor at Mount Sinai.

It was some of the first strong biological support for the gateway hypothesis, Nestler says, helping convince researchers, educators, and policymakers that biology was part of the picture.

SPEAKING TO THE AUDIENCE of educators in June, Hurd painted cannabis dependence as a biological condition. “Many people think, ‘Oh you can’t become addicted to cannabis,’” she says, “but when you look at the numbers out there, cannabis use disorder is actually quite common.” Estimates vary widely, but up to 30% of users become unable to stop using the drug despite negative effects on their health and well-being, according to the National Institute on Drug Abuse.

Adolescents are especially vulnerable, Hurd told the Zoom audience, because the endocannabinoid system—a network of natural signaling molecules structurally similar to THC, along with their receptors—plays a central role in brain development. It fine-tunes the maturation of the prefrontal cortex, a brain area involved in self-control and decision-making. In 2019, Hurd and her colleagues reported that repeated THC exposure during adolescence in rats changed the shape and function of neurons in the animals’ prefrontal cortex. In her presentation, Hurd showed a neon green–and–yellow neuron with sparse, stunted branches next to its much bushier normal counterpart. The simpler structure, Hurd explained, means fewer contacts with other neurons.


Her study also revealed a pattern of gene expression in the rats’ THC-exposed neurons that overlapped significantly with gene expression profiles seen in people with schizophrenia. It was a hint that early cannabis use might sometimes pave the way to this psychiatric disorder, as epidemiological studies have suggested. Human studies also support concerns that early use might have lasting effects. A longitudinal study of 799 European adolescents published in 2021 linked cannabis use with a thinning of the prefrontal cortex in regions where cannabinoid receptors are expressed, and with higher levels of impulsiveness.

Yet much is not known about adolescent risk, Tapert says. She adds that a longitudinal look at nearly 12,000 U.S. children called the Adolescent Brain Cognitive Development Study, launched in 2016, should provide critical data on how cannabis use interacts with characteristics such as a person’s genetics, history of trauma, stress, and family mental health history.

However such factors shift the balance, the increasing potency of cannabis likely adds to the risks. In a 2022 paper published in Molecular Psychiatry, Hurd along with Jacqueline-Marie Ferland, a neuroscientist in her lab, reported that exposure to high-dose THC (equivalent to a strong recreational human dose of about 20 milligrams, or four typical gummies), but not low-dose (equivalent to one 5-milligram edible), once every 3 days made rats unusually sensitive to environmental stressors such as isolation. After such stress, the rats tended to avoid other animals—a sign of social anxiety—and to consume more sugar than controls, indicating increased sensitivity to reward. Earlier this year, Ferland, Hurd, and their colleagues reported in JAMA Psychiatry that high-dose THC also caused rats to make risky decisions in a “rat gambling task,” in which a rat must choose between risky and safe strategies for winning sugar pellets, behavior similar to that seen in human study participants with cannabis use disorder gambling for money.


The opening of the first recreational cannabis dispensary in New York City in December 2022 drew long lines. Inside, a worker organized jars of cannabis flower. REUTERS/EDUARDO MUNOZ
The opening of the first recreational cannabis dispensary in New York City in December 2022 drew long lines. Inside, a worker organized jars of cannabis flower. REUTERS/EDUARDO MUNOZ

High- and low-dose THC also have distinct effects on the rat brain, they showed. High doses altered the shape of neuronal support cells called astrocytes and caused changes in gene expression that suggest disruptions to signaling by the inhibitory neurotransmitter GABA.


Low-dose consumption, on the other hand, primarily distorted the shape and gene-expression patterns of neurons and spurred changes in the opioid system. It’s not yet known whether such changes also happen in the human brain, but Hurd thinks the rat studies hint at worrisome biological connections between cannabis use and neurotransmitter systems involved in a wide range of behaviors.


IN A 2019 STUDY, 7% of girls and women ages 12 to 44 reported using cannabis while pregnant. That proportion doubled between 2002 and 2017, the researchers found, and it may be even higher today. The fetus, inevitably, is exposed: THC readily passes through the placenta to the fetal brain.


To look for possible effects, Hurd began a collaboration in the early 2000s with Diana Dow-Edwards, a neuropharmacologist at the SUNY Downstate Health Sciences University. At the time, Dow-Edwards had access to fetal tissue from women with a history of drug use who had chosen to have an abortion. In women who had smoked cannabis, Hurd and Dow-Edwards found alterations to the fetal brain’s dopamine system, including reduced expression of dopamine receptors in the amygdala and nucleus accumbens, a reward center. The finding hints that in utero cannabis exposure could interfere with emotional regulation and boost vulnerability to addiction.

It’s just part of the havoc the two researchers uncovered in the fetal brain. THC reshuffled gene expression in its natural opioid system. It also tampered with the cytoskeleton, or internal scaffold, of developing neurons, reshaping their long extensions and thereby altering the neuronal wiring in parts of the fetal cerebral cortex.


When Hurd’s group tried to re-create the effects of maternal cannabis use in rodents, they saw behavioral consequences. Male rats exposed to THC in the womb more readily self-administered heroin as adults than controls. And in work published just last year in Biological Psychiatry, rats exposed to THC in utero showed low motivation, depressionlike traits, and increased sensitivity to stress as adults.


The cannabinoid type 1 receptor, a target for the psychoactive ingredient in cannabis, is found throughout the adult human brain (warm colors represent higher concentrations).YASMIN HURD
The cannabinoid type 1 receptor, a target for the psychoactive ingredient in cannabis, is found throughout the adult human brain (warm colors represent higher concentrations).YASMIN HURD

Soon after she arrived at Mount Sinai, Hurd got the opportunity to find out whether something similar happens in children exposed to cannabis in utero. A young assistant professor there, Yoko Nomura, had started an ambitious longitudinal study of pregnant women to examine how various aspects of the prenatal environment such as stress, toxins, and maternal obesity affect children. Nomura kept running into Hurd at meetings and was immediately drawn to her affable personality. “She is very approachable,” says Nomura, now a professor of psychology at Queens College at the City University of New York. The two joined forces.

For 15 years, Nomura, Hurd, and their colleagues followed the women and their 724 children, evaluating them annually. They also sequenced mRNA in their placentas to monitor the activity of thousands of genes. In a paper published in 2021 in the Proceedings of the National Academy of Sciences, Hurd, Nomura, and their colleagues reported that mothers’ cannabis use was associated with hyperactivity and heightened anxiety and aggression among their children at ages 3 to 6, along with increased cortisol, a stress hormone, in hair samples. It also reduced expression of placental genes involved in immune function, which the endocannabinoid system helps regulate. These changes correlated with the children’s future anxiety and hyperactivity levels.

Superstorm Sandy, which hit the New York metropolitan area in 2012, enabled Hurd and Nomura to show that stress exacerbates these prenatal effects. Women who were pregnant during the storm used cannabis at high rates, likely as a coping mechanism, and in the years since, their children have shown signs of trouble. At ages 2 to 5, Hurd and Nomura reported in May, these children were 31 times more likely to meet the criteria for disruptive behavior disorders and seven times more likely to have an anxiety disorder than kids exposed to neither cannabis nor Sandy in utero. “It’s a drastic synergistic increase,” Nomura says.

That work suggests the effects of cannabis on children may also be amplified in communities and families with “much greater psychosocial challenges,” Hurd says. These may include neighborhoods of color beset by poverty, violence, and a disproportionate number of arrests, she says.

ALARMED AS SHE IS about these many risks, Hurd does not support rolling back legalization. Criminalizing cannabis possession, she notes, has exacted disproportionate costs to communities of color. It also hurts people grappling with drug addiction. “It’s absurd in a civilized society that we think that locking people up for substance use will cure the problem. It actually worsens the problem,” she says. Instead, she favors regulations that limit potency and using tax revenues from the sale of cannabis to educate people about the risks, and for treatment and research to help those harmed by its use.

Hurd spends much of her time fighting for space for Mount Sinai’s addiction treatment centers. It’s a constant, depressing battle against the stigma of substance use disorders, she says, despite an overdose epidemic that has gripped the nation. A big part of the problem is money. “Addictions are not a clinically profitable specialty,” she says.

But she’s determined to keep fighting. “There are a lot of people who have a substance use disorder who would give everything to get back a normal life. Everything,” Hurd says. “That’s why I’m so committed to this career. It’s to help give people their lives back.”

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