At the right dose, cannabis has relaxing effects that can help ease anxiety and manage pain. The right dose is notoriously hard to determine, however, and just a little too much can produce a dramatically opposite effect: an experience that recreational users sometimes call “paranoia,” an acute anxiety and panic that makes the world feel hostile and terrifying. Such acute anxiety is commonly reported by people seeking emergency care for cannabis-induced intoxication.
But one of the many aromatic compounds found naturally in the cannabis plant may actually ease these anxiety-inducing effects, according to new research published this month in Drug and Alcohol Dependence. The findings suggest that cannabis strains with a high concentration of this citrusy compound, called d-limonene, could help some users avoid anxious reactions and thus benefit more from marijuana’s therapeutic potential.
Cannabis plants contain more than 500 chemical compounds. The cannabinoid tetrahydrocannabinol (THC) is the one that causes the high, and other cannabinoids (such as cannabidiol, or CBD) are widely believed to affect the experience as well. The plant also contains hundreds of aromatic compounds called terpenes, which give it its distinct scent profile. For decades, researchers, growers and cannabis enthusiasts alike have speculated that there’s something special about the effect of consuming products made from whole flowers rather than single compounds—such as THC or CBD—selectively isolated from the plant. This “entourage effect” concept arose from experiments that seemed to show whole-plant products produced a different experience than THC alone.
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The idea is “that the whole is greater than the sum of its parts, that there’s synergy,” says Ryan Vandrey, a behavioral pharmacologist at Johns Hopkins University and senior author of the new study. But scientists don’t know if this effect works or how it might do so, largely because of the sheer number of chemicals involved.
Despite the lack of clear scientific evidence for the entourage effect, this idea has had a major impact on how the industry breeds and markets different cannabis strains, Vandrey says. There are “a lot of claims made by businesses about the effects of certain types of cannabis products without empirical data to back it up,” he says. Some of these claims point back to a 2011 review paper by psychopharmacology researcher Ethan Russo, now CEO of CReDO Science and a co-author of the new study. Russo’s 2011 paper cited studies on animals and humans (in noncannabis contexts) that indicated the terpene d-limonene has anxiety-reducing properties. The question of whether it has the same impact in cannabis consumption had never been tested, however. So Russo called Vandrey and asked if he would be willing to do an experiment.
“I was a heavy skeptic going into this study,” Vandrey says. He didn’t expect to see that these “relatively small concentrations of compounds” would have a substantial impact on the overall effects of cannabis. To test whether they would, he and his team recruited participants who were not regular cannabis users but reported having an anxious reaction to the drug in the past. Twenty participants completed nine randomized tests in which they inhaled combinations of different levels of vaporized THC and d-limonene or a water-vapor placebo. The investigation was a double-blind study, so neither the participants nor the researchers knew which active compounds, if any, the participants received at any point. (The participants exhaled through a filter so they couldn’t guess based on the smell.) Afterward 12 of the 20 participants completed an additional test in which they received even higher doses of d-limonene, along with THC.
During each test, researchers sampled the participants’ blood several times. Before, immediately following and at regular intervals for six hours after drug exposure, participants were asked to rate the effects and their mood. Researchers also noted their vital signs and tested cognitive performance.
The scientists found that as d-limonene concentration increased in proportion to THC, participants reported fewer anxiety symptoms. This result was most pronounced in the final trial, when participants inhaled one part of d-limonene for two parts of THC—a very high ratio that would not occur naturally in any known strain of cannabis.* “This is early-stage stuff, but the cool thing is that it worked—and even cooler, it was a very specific effect,” Vandrey says. Besides reducing participants’ feelings of anxiety or panic, d-limonene levels didn’t appear to alter any other part of the THC’s reported effects. “This seems to be a very targeted effect,” he says.
Such investigations are “exactly the kind of controlled studies we need to inform the benefits [and] risks of cannabis,” says Deepak Cyril D’Souza, a psychiatrist at Yale University, who is researching the drug. Given the high concentrations of d-limonene tested in the new study, however, he cautions consumers against seeking out the terpene on the basis of this research alone—and warns that “commercial interests may capitalize on this like they have done with CBD.”
Although researchers don’t know exactly why d-limonene might reduce THC-induced anxiety, studies conducted in rodents suggest the chemical tweaks levels of the neurotransmitters serotonin, dopamine and gamma-aminobutyric acid (GABA) in the brain. Importantly, d-limonene does not directly interfere with how THC acts on the brain—which is likely why it doesn’t impact the other aspects of the high, Vandrey says.
The new study is the first of its kind, so it has a few key limitations. Participants inhaled a vaporized version of the drug, so the findings may not apply to other methods of consumption (such as smoking or eating). And the effect of vaporized d-limonene in the lab was less notable at concentrations that one would find naturally in cannabis. Yet Vandrey notes that that effect could also have been lower than that of d-limonene consumed in a typical, private smoking environment. When one smokes weed, much of the effects of such aromatic compounds come from continuing to smell them after the initial exhale. But as noted, the study’s participants had to breathe out through a filter to disguise the scent.
Future studies could help untangle how these many compounds interact with one another. Right now “there is not enough information on terpene interactions in the body,” says Uma Anand, a neuroscientist at Imperial College London, who has studied how isolated cannabis terpenes impact rat neurons. Vandrey’s team is currently running similar experiments with other terpenes found in cannabis, including α-pinene and β-myrcene. (While his lab hasn’t fully analyzed the α-pinene data yet, it doesn’t appear to affect anxious responses so far.)
More research on the effects of terpenes could potentially lend credence to some common folk remedies for weed-induced paranoia, such as chewing on lemon peels, pine nuts or peppercorns—all of which contain terpenes found naturally in cannabis. In fact, people have been using citrus fruits as an antidote for cannabis’s undesired effects since at least the 10th century C.E., when the remedy was employed in Persia, Russo noted in his 2011 paper. In 1848 Scottish toxicologist Sir Robert Christison documented using such an approach after he consumed cannabis for a toothache:
“Next morning,” Christison wrote,“there was an ordinary appetite, much torpidity, great defect and shortness of memory, extreme apparent protraction of time.... These symptoms lasted until 2 P.M., when they ceased entirely in a few minutes after taking lemonade.”
*Editor’s Note (5/15/24): This sentence was edited after posting to correct the ratio of d-limonene to THC that showed the most pronounced result.