New Insight into Neurobehavioral Effects of Legalized Cannabis

Michael Vlessides

July 10, 2020

Researchers have published one of the first studies to characterize the association between the consumption of legal cannabis and subsequent pharmacologic and neurobehavioral outcomes, with somewhat surprising results.

The study showed that although cannabis consumption did not affect most short-term neurobehavioral measures, it delayed recall memory and impaired balance.

The investigation also showed that users of much more potent cannabis concentrates actually demonstrated similar or lower levels of subjective drug intoxication and short-term impairment than their counterparts who used lower-potency forms of the cannabis flower.

"It does not appear that the potency being used matters that much," senior investigator Kent E. Hutchison, PhD, told Medscape Medical News. "People seem to be titrating to a certain level of intoxication or a certain level of feeling high. And for some people that requires a lot of drug, and for other people not as much."

"As a first study, this was very useful in the sense that nobody really knew the effects of high-potency cannabis products," added Hutchison, a professor of psychology and neuroscience at the University of Colorado Boulder.

The study was published online June 10 in JAMA Psychiatry.

Widespread Availability, Little Research

Recreational cannabis is now legal in 11 states and the District of Columbia, while medical cannabis is legal in 33. However, despite its growing popularity, there is little research on the potential health and biobehavioral risks of cannabis, largely because of federal restrictions on cannabis research.

Cannabis users typically consume various forms of the cannabis flower, which can boast concentrations of the psychoactive cannabinoid delta-9-tetrahydrocannabinol (THC) of up to 30%. However, use of concentrated forms of cannabis — which are made by extracting plant cannabinoids into a different form — is increasing.

Such formulations can boast THC concentrations as high as 90%. Nevertheless, data regarding the relative risks of these higher-strength products is limited.

Previous research has shown a variety of negative short-term and long-term neurobehavioral effects associated with cannabis use, including harmful cognitive and motor effects.

Extended exposure to THC may also negatively affect brain regions that are associated with the control of coordinated movement, and create brain-activation deficits in motor control regions that persist well beyond the effects of short-term intoxication.

Despite such findings, Hutchison said the existing literature on the subject does not yield a real-world view of current cannabis use, as it tends to focus on low-THC products that are increasingly less common in today's legal market.

Given such shortcomings, the investigators wanted to address persistent questions surrounding the neurobehavioral effects of legal cannabis flower products (16% or 24% THC) and cannabis concentrate products (70% or 90% THC). In doing so, they examined three primary topics:

  • The association between short-term use of these products and THC plasma levels; subjective intoxication; and mood, cognitive performance, and balance

  • Differences in such associations between users of cannabis flower and concentrate products

  • Potential variations in these associations by THC potency

High- vs Low-Potency Varieties

The study included 133 individuals (ages 21-70), who were designated as either cannabis flower users or cannabis concentrate users.

Participants had all used cannabis at least four times in the previous month with no adverse reaction, and were not receiving treatment for a psychotic disorder or bipolar disorder.

Participants were randomly assigned to consume either higher-potency or lower-potency products that had been purchased from a local dispensary.

Flower users were randomized to purchase 3 g of either a 16% THC or 24% THC product, while concentrate users were randomized to purchase 1g of either 70% THC or 90% THC.

Participants completed a series of four assessments, one at baseline and three others at a mobile laboratory. The mobile laboratory assessments occurred before, immediately after, and one hour after participants had all consumed their cannabis ad libitum.

Of the original cohort of 133 participants, 55 flower cannabis users (mean age 28.8 years; 46% women) and 66 concentrate cannabis users (mean age 28.3 years; 45% women) complied with the study's instructions and had complete data.

The study's primary outcome measures included plasma cannabinoids, subjective drug intoxication and mood, and neurobehavioral outcomes such as attention, memory, inhibitory control, and balance.

Mixed Results

With respect to cannabis concentrations, results showed that users of concentrate exhibited higher levels of both plasma THC and the active metabolite of THC (11-hydroxyΔ9-THC) across all points than their counterparts who used cannabis flower products.

Specifically, mean plasma THC levels were 1016±1380 μg/ml in concentrate users and 455±503 μg/mL in flower users after ad libitum cannabis consumption. Nevertheless, self-reported levels of intoxication were no different between users of cannabis flower or concentrate products.

Although results also showed that most neurobehavioral measures were not altered by short-term cannabis consumption, there were some notable exceptions. There was a negative linear effect with delayed verbal recall errors, suggesting poorer performance after cannabis use (F1, 203 = 32.31; P < .001).

On the other hand, investigators found a positive linear effect with inhibitory control and working memory, which actually suggests better performance after cannabis use. This finding, the researchers note, may be the result of a practice effect. Cannabis flower users performed better across all inhibitory control assessments.

The researchers also tested participants' balance with their eyes open and closed. In the eyes-open condition, they found a trend toward impaired balance after cannabis use, though this normalized within an hour.

When subjects closed their eyes, however, researchers observed a significant short-term increase in sway after cannabis use, which fell back to pre-use levels one hour after use (F1, 203 = 18.88; P < .001) were impaired after use.

Of note, outcomes did not differ between groups according to the type of cannabis product consumed or its relative potency.

The study yielded several surprising findings, beginning with self-reported intoxication levels, which were not statistically significant between different cannabis flower and concentrate users, despite significantly different plasma THC levels between the two groups.

Hutchison explained that this may be the result of greater THC tolerance among concentrate users, THC saturation of cannabinoid receptors, or inter-individual differences among users with respect to cannabis metabolism or sensitivity.

"I thought for sure that high-potency users would be much more compromised," he said. "I guess it just goes to show we have a lot to learn about how these things work."

Additionally, there were virtually no significant changes in acute performance after cannabis use, with the exception of delayed verbal recall. In fact, the most marked change observed in the study was the effect of cannabis on balance immediately after drug use, though these changes seemed to abate within an hour.

Nevertheless, the study highlights several potential public health implications of cannabis consumption, Hutchison added. "What happens when people with high blood concentrations decide to quit?" he asked. "Do they have trouble quitting? Do they have withdrawal symptoms?"

The long-term effects of cannabis use is another important question that still needs to be answered, he added.

Finally, Hutchison noted that although the study showed little difference between users of cannabis flower and concentrates, study participants were all experienced users.

"There is certainly the potential for harm when a naive person uses cannabis concentrate," he said. "Suddenly they have way more THC than they thought they were going to get, and that's where a lot of people get into trouble with cannabis."

Pitfalls and Hurdles

In an accompanying editorial, Margaret Haney, PhD, of Columbia University Irving Medical Center, New York City, explained that cannabis' awkward position as simultaneously legal and illegal, medical and recreational, has hampered researchers' ability to study its effects as comprehensively as they would otherwise like.

"With a federally illegal drug legalized in individual states, scientists constrained, and federal agencies somewhat silent, clinicians have none of the data that guide their decisions for other medications (eg, which indication, product, cannabinoid ratio, dose, or route of administration; what risks for individual patients [eg, pregnant, adolescent, psychiatric?])," Haney writes.

These pitfalls are compounded by the significant regulatory hurdles.

"The FDA is appropriately cautious about what it allows scientists to test in patients and none of the products available in dispensaries or online have undergone the safety and manufacturing procedures needed for FDA approval," she continued. "How then to conduct the studies so needed?"

Yet as Haney noted, giving cannabinoid researchers a Schedule I exemption may help address many of the barriers facing these scientists. Such a move, she said, would increase the number of randomized controlled trials being performed, "and thereby begin to breach the divide between the use of these products and empirical evidence."

Hutchison has disclosed no relevant financial relationships. Haney disclosed funding from the US National Institute on Drug Abuse and from the Thompson Family Foundation Initiative. The study was funded by the NIH and Colorado Department of Public Health and Environment.

JAMA Psych. Published online June 10, 2020. Abstract, Editorial

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