Most drugs come with their fair share of tall tales. These range from the fearful to the reverent, granting these substances powers that do not align with their actual effects. Cannabis is one drug that has been both understudied and over-mythologized.

“Cannabis has been around for a long time, but it has not been well studied,” said Harriet de Wit, PhD, a Professor in the Department of Psychiatry and Behavioral Neuroscience at the University of Chicago. “People have decided for themselves what it’s good for. It’s hard for us to know how much of those effects are pharmacological or just expectancy.”

As cannabis legalization and access expands, it becomes increasingly crucial for people to understand it more fully. Part of this understanding requires learning how cannabis can uniquely impact different populations.

De Wit is studying the effects of THC — the main psychoactive ingredient in cannabis — in specific groups of people. Her research team recently released two papers on the effects of cannabis in women and adolescents. The studies measured real-time effects of THC in human participants in tightly controlled settings. They found that increasing doses of THC can increase bodily anxiety in women, and that compared to adults, adolescents are more negatively impacted by THC on cognitive tasks.

Not your mother’s high: THC has different effects in teens

Conor Murray, PhD, became interested in studying THC from the historical use of cannabis and other plants as instruments for spiritual experiences. Cannabis has been used for spiritual purposes around the world for several thousand years. It has had roles in celebration, healing, communication with gods, sexual practice, and philosophy. Most of these ancient uses of cannabis continue in the modern day, and the drug is only growing in popularity. Yet one use case of cannabis has been consistently low — in scientific studies.

“It became clear to me that cannabis is greatly understudied,” said Murray. “I wanted to understand what exactly the drug does to the brain and cognition, to what extent those effects represent an enhancement or impairment of cognition and awareness, and in which individuals they are most pronounced.”

What scientists do know is that THC binds to a specific receptor in the brain — the cannabinoid type 1 receptor (CB1R). CB1R levels fluctuate over a lifetime, with the peak between 15 and 17 years of age. CB1R is also concentrated in the forebrain, the region most responsible for cognition. What scientists do not know is whether the larger quantities of CB1R earlier in life mean that adolescents are more sensitive to cannabis.

As a postdoctoral fellow in the de Wit lab, Murray sought to answer this question. He recruited adolescents (age 18-20) and adults (age 30-40) for a three-session study. In each session, subjects received a placebo, low THC dose (7.5 mg), or high THC dose (15 mg) orally. Neither subject nor researcher knew which of the three they were receiving at the time. Subjects across groups were matched for several important factors, such as sex, weight, and tolerance to cannabis, which was measured by the frequency and total instances of cannabis use.

During all sessions, Murray recorded three types of data: 1) EEG, a physical signature of cognition, 2) performance on several cognitive behavioral tasks; and 3) subjective answers to questionnaires. All were meant to capture what was going on in the subjects’ brains from different angles.

To gather EEG recordings, 128 electrodes were placed on participants’ heads as they either rested with eyes closed or engaged in an attention-demanding task. The electrodes picked up brain waves, which are a result of electrical activity across neurons. Different frequencies of waves are known to signify different types of cognitive processes. The alpha wave is a mid-range frequency that is strongest during relaxation and reduced sensory input, such as closing of the eyes.

It takes synchronous activity to create the alpha waves across the brain, “Like all the neurons are in a choir singing the same song,” said Murray. He laughed and continued, “Like they’re all at rest, saying ‘Om’. But as soon as they need to do a job, like making sense of the visual field when you open your eyes, they start chattering with each other — you can’t hear the synchronous activity anymore.” Alpha waves are much weaker in brains that are engaged in demanding tasks, which require individual neurons to “chatter” with one another.

Adolescents have a harder time breaking out of the THC “trance”

In the study, Dr. Murray found that the adults had lesser alpha power than adolescents during resting state regardless of drug dosage. “My interpretation is that as you become an adult, you’re able to carry on individual conversations between neurons much more readily,” said Murray, which is needed for proper task execution and breaks up the synchronous alpha wave.

THC had no detectable effect on brain waves at rest in either the adults or adolescents, but the differences in how THC affects the brain and cognition between the age groups became clear during task performance. Specifically, when adolescents consumed THC, they were less capable than adults of exiting the alpha wave state during task engagement. It’s as if “THC forces them to remain in a trance-like, meditative state,” said Murray.

The adolescents’ difficulty in exiting the THC trance was reflected in four other tasks. The tasks required subjects to stay attentive, react rapidly — or stop themselves from reacting too rapidly, recall the recent past, and judge how much time has passed. Cannabis commonly causes time dilation, in which one minute can feel more like ten. Across tasks, adolescents performed more poorly than adults, and performance further declined when the THC dose was higher. “We actually had to remove one of the adolescents from analysis because they were so intoxicated they could not proceed with the task,” said Murray.

Throughout the session, participants completed a series of questionnaires on their subjective experience. While adolescents experienced significant negative effects on their cognitive performance, they did not differ from adults in their feelings about the drug’s subjective effects, stating similar feelings of like/dislike, awareness of intoxication, and mood state during the sessions.

This result could be a crucial piece of the policy puzzle surrounding cannabis. While adolescents may not feel any more intoxicated by cannabis than adults, their behavior could be more negatively impacted. This has implications for use of cannabis in conjunction with tasks like driving, which could be more dangerous for adolescents, or in a school setting, where adolescents may not be able to learn or demonstrate learning as effectively.

In addition, this study powerfully links the biochemical and cognitive levels of the human brain, as the higher concentrations of one receptor in adolescents — CB1R — is reflected in their cognitive performance. This might also help explain why adolescents have a greater affinity to cannabis, if experiencing “headier” effects than adults, said Murray. “Generally, the brain may respond differently to different drugs at different times in life, and adolescents may naturally grow out of cannabis use as reinforcing effects wane.”

Some receptors have the opposite pattern to CB1R: the levels of dopamine 1, the receptor responsible for the effects of cocaine and methamphetamine, increase in adulthood. Different drugs could pose the highest risk to different age groups. Further studies could guide evidence-based policy decisions rooted in the facts about drugs and their dangers instead of fearful myths.

Gender and hormones may play a role in THC’s effects 

Adolescents may not be the only group to experience a unique effect from THC.

“So much of what we believe is based on studies in males,” said de Wit. “A lot of knowledge may not hold true in females.” Historically, subjects in animal and human studies — across all of science — have been male. Researchers have claimed that it is too difficult to control for the fluctuating hormones in the female body. Yet this is why it is crucial to include women as subjects - to understand the differences and potential risks when hormones enter the picture. It is dangerous to assume that all results in male bodies are universally true. Many individuals also take hormones as birth control or to affirm gender identity. These external hormones could interact with medical treatments and drugs as well.

As a PhD candidate in the de Wit lab, Elisa Pabon, PhD, did not shy away from the challenge of hormones. Her paper is one of the first to examine the effects of THC specifically in women, and is part of a larger study on the interaction of THC and the menstrual cycle. In animal studies, responses to THC differ between males and females, and THC sensitivity depends on the level of the female hormone estradiol. By studying women at a specific phase of the menstrual cycle, Pabon found that increasing doses of THC increases physical signs of anxiety.

Similar to Murray’s study design, Pabon’s participants were given either a placebo, low THC, or high THC dose across three sessions. All participants were cisgender adult women with regular menstrual cycles and were, at the time of the sessions, in the follicular phase. This is the longest phase of the cycle and starts on the first day of a period and lasts until an egg is released.

To measure drug effects, Pabon used questionnaires and electrocardiogram (ECG) recordings of the heart and circulatory system. Together, they measured subjects’ physical and psychological levels of anxiety.

THC produces physiological symptoms of anxiety in women

Outside of the brain, one half of your nervous system acts largely unconsciously. This is the autonomic nervous system, which is in charge of important functions such as keeping your heart beating and intestines digesting. Pabon and her colleagues found that two autonomic heart measures - heart rate and high frequency heart rate variability — were related to THC dose.

While heart rate measures how fast your heartbeat is at any point in time, heart rate variability measures how fast your heart rate changes over a longer period. It quantifies the health of your blood vessels — the healthier they are, the more flexible they’ll be, and the more rapidly your heart rate can change.

Pabon found that larger THC doses increased heart rate and decreased heart rate variability. Both are indicators that physical anxiety increases in women due to greater THC. Yet curiously, these measures were not associated with subjective feelings of anxiety.

Six times during each session, participants completed questionnaires, which included assessments for cannabis-specific effects (such as “I notice that my heart is beating faster” and “My thoughts seem to come and go”) and anxiety. At the higher THC dose, subjects reported greater cannabis effects, but not anxiety effects. So, while physical responses to higher doses of THC are reflected in subjects’ feelings, anxiety is not one of them.

De Wit admitted that the findings were curious, but suggested that the mismatch between physical and subjective measures is not too surprising. “There are theories that people report anxiety when they have an increased sense of heart rate,” she said. “When they feel their heart rate increasing, they will interpret that as anxiety.” Subjects in the study did have higher heart rates at higher THC doses and noticed it themselves, but they did not self-associate it with anxiety.

However, others using cannabis in the real world might link their increased heart rates with anxiety, leading to a self-fulfilling cascade. In addition, “any drug can work in a variety of different ways,” de Wit said. “The receptors and pathways that account for the psychological effects to THC might differ from the physiological. The mechanisms might be dissociated.” So, to equate autonomic nervous system activity with anxiety is an incomplete story.

“It’s important for us to understand what variables influence responses to drugs,” said de Wit. And if sex and hormones are not variables of concern for THC anxiety responses, she said that is an “important result from a scientific and safety point of view.” It is too soon to rule out the impact of hormones altogether. All subjects in Pabon’s study were in a specific phase of the menstrual cycle, and a direct comparison with male participants has yet to be made. However, this study lays the groundwork for measuring physical and subjective drug effects side-by-side in different populations. It is a pioneering piece in characterizing human responses to cannabis more fully.

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The study, "Adolescents are more sensitive than adults to acute behavioral and cognitive effects of THC", was published February 2, 2022 in Neuropsychopharmacology. It was supported by the National Institutes of Health (DA02812, T32DA043469). Additional authors include Zhengyi Huang and Royce Lee, both of the University of Chicago.

The study, "Acute effects of oral delta-9-tetrahydrocannabinol (THC) on autonomic cardiac activity and their relation to subjective and anxiogenic effects", was published October 19, 2021 in Psychophysiology. It was supported by the National Institute on Drug Abuse (R01DA002812, F31DA049391) and the National Institutes of Health (T32DA043469). Additional authors include Frederica Rockwood and Greg J. Norman, both of the University of Chicago.

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