Cannabis Compound Curbs Anxiety

Summary: A new study illuminated the anxiety-reducing potential of d-limonene, a natural component of cannabis, when combined with THC. The research showcases how vaporized d-limonene can mitigate the anxiety and paranoia often induced by THC, opening avenues for safer medicinal and recreational cannabis use.

Through a controlled experiment involving 20 healthy adults, the study demonstrates that d-limonene, in increasing doses, significantly lowers subjective anxiety without affecting THC’s cognitive or euphoric effects. This discovery not only enhances the understanding of cannabis’s complex pharmacology but also hints at new strategies for improving cannabis therapy and safety.

Key Facts:

  1. d-Limonene, a common terpene in cannabis, was shown to reduce THC-induced anxiety in humans significantly.
  2. The study involved 20 participants in a double-blinded setup, testing various combinations of THC and d-limonene, showing that higher doses of d-limonene led to greater reductions in anxiety.
  3. This research could lead to safer cannabis use by potentially developing THC products that incorporate d-limonene to mitigate anxiety effects, with a patent application already submitted based on these findings.

Source: Johns Hopkins Medicine

A Johns Hopkins Medicine-led research team has added to evidence that a chemical found naturally in cannabis (also known as marijuana) can — in the right amounts — lessen the anxiety-inducing effects of tetrahydrocannabinol (THC), the primary psychoactive sister chemical found in cannabis.

The finding has the potential to advance the medicinal use of THC, and reduce the risks of its recreational use in some people.

This shows a woman and leaves.
They found the addition of d-limonene significantly reduced overall ratings of feeling “anxious/nervous” and “paranoid” compared with rating the effect of THC alone. Credit: Neuroscience News

The substance, called d-limonene, is one of the most abundant terpenes, or essential oils, in the cannabis plant, and has shown promise in rodent studies in reducing anxiety behaviors. However, there has been little research on d-limonene or other terpenes in humans. As a group, terpenes are responsible for the taste, aroma and color of plants.

In a recent study, first published online April 1 in the Journal of Drug and Alcohol Dependence, investigators tested the effects of vaporized d-limonene alone and mixed with THC to examine the anxiety-reducing effects in humans.

They found the addition of d-limonene significantly reduced overall ratings of feeling “anxious/nervous” and “paranoid” compared with rating the effect of THC alone.

As cannabis legalization becomes more prevalent, its use for both medicinal and non-medicinal purposes is expanding rapidly. In recent years, selective breeding of cannabis plants has resulted in strains that contain upwards of 20% – 30% THC, compared with an average of 12% a decade ago. This may make it more difficult for users to be consistent with the amount of THC they consume on a given occasion.

THC interacts with receptors in the brain to produce feelings of relaxation and euphoria. However, researchers say that when a user is exposed to higher-than-usual doses of THC, the drug can also trigger anxiety, fear and panic.

“People use cannabis to help reduce anxiety, depression and post-traumatic stress disorder, but since THC levels vary widely, if a person overshoots their tolerance of THC, cannabis can induce anxiety rather than relieve it,” says study senior author Ryan Vandrey, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

“Our study demonstrates that d-limonene can modulate the effects of THC in a meaningful way and make THC more tolerable to people using it for both therapeutic and non-therapeutic purposes.”

In the study, 20 healthy adults with a median age of 26 participated in up to 10 outpatient sessions, during which they inhaled vaporized d-limonene alone, vaporized THC alone, vaporized THC and d-limonene together, or vaporized distilled water (as a placebo).

The study was double-blinded, meaning neither the researchers nor participants knew who was receiving which mixture. Twenty participants completed nine test sessions, while 12 participants also took part in an optional tenth session of THC combined with a triple-dose (15 milligrams) of d-limonene to test the extreme extent of the essential oil’s dose response curve. This was conducted after appropriate safety data were obtained from the lower doses (1 milligram and 5 milligrams).

In all participants, the researchers measured subjective drug effects, subjective ratings of mood, vital signs (heart rate and blood pressure) and cognitive performance (measures of memory, psychomotor ability and attention) at baseline, and then an additional nine times after initial exposure over the course of each of the six-hour test sessions.

They also collected blood and urine samples from each subject before, during and after each six-hour session to test for THC and d-limonene levels.

The research team concluded that combining d-limonene with THC significantly reduced subjective indicators/reports of THC-induced anxiety in participants. These reductions were greater as the dose of d-limonene was increased.

Additionally, they saw no interference with THC’s subjective, cognitive or physiological effects when co-administered with d-limonene, as well as no effects from d-limonene alone that differed from the placebo test.

“This study is a first step in uncovering how we can mitigate risks of THC when used in medicine, and also is targeted at making cannabis safer for the general, non-therapeutic consumer,” says study lead author Tory Spindle, Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

The researchers plan to continue experimenting with other terpenes alone and in combination with THC to see how they interact with each other, as well as replicate the d-limonene study in larger and more diverse clinical populations. They also plan to test alternative methods of administration, such as oral ingestion.

Along with Vandrey and Spindle, members of the study team from Johns Hopkins Medicine are George Bigelow, Lauren Pollak and C. Austin Zamarippa. Other team members are Ethan Russo at CReDO Science, and Uwe Christians, Jost Klawitter, Cristina Sempio, Touraj Shokati, Bridget Tompson and Alexandra Ward at the University of Colorado Anschutz Medical Campus.  

Spindle has served as a consultant for Canopy Health Innovations Inc. and has received research funding from Cultivate Biologics. Vandrey has served as a consultant or received honoraria from Mira1a Therapeutics Inc., Jazz Pharmaceuticals, Charlotte’s Web, Syqe Medical Ltd. and WebMD. Russo is the founder and CEO of CReDo Science and a scientific adviser to True Terpenes.

A patent application (PCT/US2022/014296) has been submitted by The Johns Hopkins University on behalf of Vandrey, Spindle and Russo for the use of d-limonene to reduce THC-induced anxiety, based on the data presented in this study (after the trial concluded and data were analyzed).

Funding: The other study authors do not have financial or conflict-of-interest disclosures.

About this anxiety and neuropharmacology research news

Author: Michael E. Newman
Source: Johns Hopkins Medicine
Contact: Michael E. Newman – Johns Hopkins Medicine
Image: The image is credited to Neuroscience News

Original Research: Open access.
Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis” by Ryan Vandrey et al. Journal of Drug and Alcohol Dependence


Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis


Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (THC), which is believed to drive most of its acute pharmacodynamic effects. The entourage effect theory asserts that non-THC constituents can impact acute cannabis effects, but few empirical studies have systematically evaluated this theory in humans. This study assessed whether the cannabis terpenoid d-limonene mitigates the acute anxiogenic effects of THC.


Twenty healthy adults completed nine, double-blind outpatient sessions in which they inhaled vaporized THC alone (15 mg or 30 mg), d-limonene alone (1 mg or 5 mg), the same doses of THC and d-limonene together, or placebo; a subset of participants (n=12) completed a tenth session in which 30 mg THC+15 mg d-limonene was administered. Outcomes included subjective drug effects, cognitive/psychomotor performance, vital signs, and plasma THC and d-limonene concentrations.


When d-limonene was administered alone, pharmacodynamic outcomes did not differ from placebo. Administration of 15 mg and 30 mg THC alone produced subjective, cognitive, and physiological effects typical of acute cannabis exposure. Ratings of anxiety-like subjective effects qualitatively decreased as d-limonene dose increased and concurrent administration of 30 mg THC+15 mg d-limonene significantly reduced ratings of “anxious/nervous” and “paranoid” compared with 30 mg THC alone. Other pharmacodynamic effects were unchanged by d-limonene. D-limonene plasma concentrations were dose orderly, and concurrent administration of d-limonene did not alter THC pharmacokinetics.


D-limonene selectively attenuated THC-induced anxiogenic effects, suggesting this terpenoid could increase the therapeutic index of THC. Future research should determine whether this effect extends to oral dose formulations and evaluate the interactions between other cannabis terpenoids or cannabinoids and THC.

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