New US research suggests that d-limonene, a terpene commonly found in cannabis, can reduce the anxiety and paranoia that THC sometimes triggers — provided it is administered in sufficient quantities.
D-limonene is among the most prevalent terpenes in the cannabis plant. While earlier rodent studies pointed to its potential in curbing anxiety-related behaviours, rigorous human research had been largely absent until now.
In a study published in the Journal of Drug and Alcohol Dependence, researchers at Johns Hopkins Medicine examined what happens when vaporised d-limonene is administered both on its own and alongside THC, with a focus on its anxiety-reducing properties in human subjects.
Their findings showed that adding d-limonene meaningfully lowered participants' self-reported feelings of being "anxious/nervous" and "paranoid" when compared to THC administered without it.
Senior author Professor Ryan Vandrey said: "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.
"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."
The double-blinded trial enrolled 20 healthy adults with a median age of 26, who each attended up to 10 outpatient sessions. During these visits, participants inhaled vaporised d-limonene alone, THC alone, a combination of THC and d-limonene, or distilled water as a placebo.
All 20 participants completed nine test sessions, and 12 of them opted into a tenth session in which THC was paired with a triple dose (15mg) of d-limonene to probe the upper end of the dose-response curve. This session proceeded only after safety data from the lower doses of 1mg and 5mg had been reviewed and deemed appropriate.
Throughout each six-hour session, researchers recorded subjective drug effects and mood ratings, monitored vital signs including heart rate and blood pressure, and assessed cognitive performance across measures of memory, psychomotor ability and attention — taking readings at baseline and nine additional times following initial exposure.
Blood and urine samples were also collected from each participant before, during and after every session to measure THC and d-limonene concentrations.
The researchers concluded that co-administering d-limonene with THC significantly reduced participants' self-reported THC-induced anxiety, with greater reductions observed at higher d-limonene doses.
They also found that d-limonene did not interfere with the subjective, cognitive or physiological effects of THC when the two were combined, and that d-limonene alone produced no effects distinguishable from the placebo.
Lead author Associate Professor Tory Spindle said: "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."
The team intends to extend this line of inquiry by testing other terpenes — both individually and in combination with THC — to better understand their interactions, and by repeating the d-limonene study with larger and more diverse clinical populations. Alternative methods of administration, including oral ingestion, are also planned for investigation.
Johns Hopkins University has filed a patent application on behalf of several members of the research team, covering the use of d-limonene to reduce THC-induced anxiety based on the data generated by this study.
