Cannabis use is on the rise globally, with increased legal acceptance for both medical and recreational purposes. The primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), is known for its varied effects on users, ranging from euphoria and relaxation to anxiety and paranoia. However, recent research published in the journal Drug and Alcohol Dependence suggests that D-limonene, a common terpene found in cannabis and citrus fruits, might mitigate some of the anxiety-inducing effects of THC.
The focus of cannabis research has primarily been on cannabinoids like THC and CBD. However, the cannabis plant contains numerous other compounds, including terpenes such as D-limonene, which may influence the plant’s overall effect on users. Terpenes are aromatic compounds also found widely in nature and are known for their distinctive fragrances and biological activities, which in some cases include therapeutic properties.
The concept of the “entourage effect” suggests that the therapeutic effects of cannabis are not just due to THC alone but may be enhanced, or its side effects mitigated, by other plant compounds. Despite this, research into how non-THC constituents like terpenes interact with THC has been limited and mostly anecdotal. The new study aimed to fill that gap by investigating whether D-limonene could modulate the anxiety-provoking effects of THC.
The research conducted a double-blind, within-subjects crossover study with 20 participants. This means each participant received multiple treatments (THC and D-limonene in various combinations, and placebo) across different sessions, and neither the participants nor the researchers knew which treatment was being administered at any given time. This method helps to reduce bias and allows the effects of each treatment to be compared within the same individuals, enhancing the reliability of the results.
Participants were selected based on specific criteria. They had to be adults in good health, not pregnant, non-users of drugs other than cannabis, alcohol, nicotine, or caffeine, and with a history of experiencing anxiety when using cannabis. These criteria ensured that the sample was representative of typical users who might benefit from anxiolytic interventions.
The study consisted of several sessions where participants inhaled vaporized substances through a controlled setup. Each session was spaced by at least 48 hours to prevent carryover effects from previous sessions. D-limonene and THC were administered alone and in combination at varying doses to assess their individual and interactive effects. A placebo session involved inhaling distilled water vapor to establish a baseline for comparison.
The most notable result from the study was the reduction in anxiety-like and paranoid feelings when D-limonene was administered alongside THC. The effects were particularly pronounced when 30 mg of THC was combined with 15 mg of D-limonene. This finding is pivotal because it indicates that D-limonene could potentially be used to mitigate some of the less desirable effects of THC, making cannabis use more palatable for those who may experience anxiety as a side effect.
“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,” explained study senior author Ryan Vandrey, a 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.”
Interestingly, D-limonene did not broadly alter all the effects of THC. The terpene specifically reduced feelings of anxiety and paranoia without significantly affecting other subjective, cognitive, or physiological effects induced by THC. This specificity is beneficial because it allows for the potential use of D-limonene in a targeted way
The results also showed that while D-limonene affected some of the psychological impact of THC, it did not alter the pharmacokinetics of THC (how THC was absorbed, distributed, metabolized, and excreted by the body).
These findings open up new avenues for the formulation of cannabis products. By incorporating specific terpenes like D-limonene, it may be possible to enhance the therapeutic index of THC-rich products. This could lead to the development of specialized cannabis strains or products designed to offer the benefits of THC while mitigating its potential to cause anxiety and paranoia.
Despite these promising results, the study has several limitations. The high dose of D-limonene used is not typically found in natural cannabis products, and the study did not test the entourage effects in full-spectrum cannabis products containing multiple cannabinoids and terpenes.
“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,” said study lead author Tory Spindle, an associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.
Future research could explore the impact of different ratios and forms of THC and D-limonene, including oral administrations more typical of medical cannabis use. The findings also need replication in larger and more diverse samples to understand variability in response based on individual differences such as genetics, previous cannabis use, and sex.
“This is among the first clinical studies to demonstrate the validity of the cannabis entourage effect, which theorizes that THC and other constituents of the plant interact in meaningful ways that alter acute cannabis effects,” the researchers concluded.
“Given the growing interest in the use of cannabis for medicinal purposes and expanding legalization of cannabis for nonmedicinal purposes, further understanding of which constituents may increase the safety profile of cannabis by attenuating acute adverse effects (e.g., anxiety and paranoia), and which constituents may exacerbate adverse effects, is paramount for advancing the use of cannabinoids in medicine and, more broadly, protecting public health.”
The study, “Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis,” was authored by Tory R. Spindle, C. Austin Zamarripa, Ethan Russo, Lauren Pollak, George Bigelow, Alexandra M. Ward, Bridget Tompson, Cristina Sempio, Touraj Shokati, Jost Klawitter, Uwe Christians, and Ryan Vandrey.
