Cannabis use is increasing globally, with growing legal acceptance for medical and recreational purposes. The main 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 addiction suggests that D-limonene, a common terpene found in cannabis and citrus fruits, may alleviate some of the anxiety-inducing effects of THC.
Cannabis research has primarily focused on cannabinoids like THC and CBD. However, the cannabis plant contains many other compounds, including terpenes such as D-limonene, which can influence the plant’s overall effect on users. Terpenes are aromatic compounds also widely found in nature and are known for their distinctive scents 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 solely 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 this gap by examining whether D-limonene could modulate the anxiety-inducing effects of THC.
The research conducted a double-blind, within-subjects, crossover study with 20 participants. This means that each participant received multiple treatments (THC and D-limonene in various combinations and placebo) during 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 makes it possible to compare the effects of each treatment in the same individuals, thus improving the reliability of the results.
Participants were selected based on specific criteria. They had to be healthy adults, non-pregnant, non-users of drugs other than cannabis, alcohol, nicotine or caffeine, and with a history of anxiety related to cannabis use. These criteria ensured that the sample was representative of typical users who might benefit from anxiolytic interventions.
The study included several sessions in which participants inhaled vaporized substances in a controlled setting. Each session was spaced at least 48 hours apart to avoid residual effects from previous sessions. D-limonene and THC were administered alone or in combination at different doses to evaluate their individual and interactive effects. A placebo session involved inhaling distilled water vapor to establish a baseline for comparison.
The most notable result of the study was the reduction in feelings of anxiety and paranoia when D-limonene was administered with THC. The effects were particularly pronounced when 30 mg of THC was combined with 15 mg of D-limonene. This finding is crucial because it indicates that D-limonene could potentially be used to mitigate some of the less desirable effects of THC, making cannabis consumption 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 because THC levels vary widely, if a person exceeds their THC tolerance, cannabis can cause anxiety rather than relieving it,” explained the study’s lead author, Ryan Vandrey. professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine. “Our study demonstrates that d-limonene can modulate the effects of THC significantly and make THC more tolerable for people who use it for therapeutic and non-therapeutic purposes.”
Interestingly, D-limonene did not alter all of the effects of THC overall. The terpene specifically reduces feelings of anxiety and paranoia without significantly affecting other subjective, cognitive, or physiological effects induced by THC. This specificity is beneficial because it allows potential use of D-limonene in a targeted manner.
The results also showed that while D-limonene affected some of the psychological impact of THC, it did not change the pharmacokinetics of THC (how THC was absorbed, distributed, metabolized, and excreted by the body).
These discoveries open new avenues for the formulation of cannabis products. By incorporating specific terpenes like D-limonene, it may be possible to improve the therapeutic index of THC-rich products. This could lead to the development of specialized cannabis strains or products designed to deliver 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 for entourage effects in full-spectrum cannabis products containing multiple cannabinoids and terpenes.
“This study is a first step in finding out how we can mitigate the risks of THC when used medicinally, and also aims to make cannabis safer for the general non-therapeutic user,” said lead author of study, Tory Spindle, associate professor of psychiatry and behavioral sciences at 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 results also need to be replicated in larger, more diverse samples to understand variability in responses based on individual differences such as genetics, prior cannabis use, and gender.
“This is one of the first clinical studies to demonstrate the validity of the cannabis entourage effect, which theorizes that THC and other constituents of the plant interact significantly to modify the acute effects of cannabis.” , the researchers concluded.
“Given the growing interest in the use of cannabis for medical purposes and the increasing legalization of cannabis for non-medical purposes, a better understanding of the constituents that can increase the safety profile of cannabis by mitigating adverse effects (e.g., anxiety and paranoia) and which constituents can exacerbate adverse effects, is paramount to advancing the use of cannabinoids in medicine and, more broadly, to protecting public health.
The study, “Vaporized D-limonene selectively attenuates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who use cannabis intermittently,” 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.