D-Limonene in cannabis may reduce tetrahydrocannabinol-induced anxiety, Study finds

A recent study published in the recent edition of Drug and Alcohol Dependence journal highlighted that d-limonene, a terpenoid found in cannabis, can reduce the anxiety-inducing effects of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of the plant. This finding challenges the existing understanding of the effects of cannabis and supports the entourage effect theory, which proposes that non-THC constituents of cannabis can significantly influence its overall impact.

This study was conducted with twenty healthy adult participants which assessed the interactions between vaporized THC and d-limonene through nine different sessions. The participants were exposed to varying doses of THC (15 mg and 30 mg), d-limonene (1 mg and 5 mg), combinations of THC and d-limonene or a placebo. An additional session with 30 mg THC and 15 mg d-limonene was conducted for a subset of twelve participants. The researchers meticulously evaluated the effects of these compounds on cognitive and psychomotor performance, vital signs, subjective drug experiences and plasma concentrations of THC and d-limonene.

The results found that while d-limonene alone did not produce significant pharmacodynamic outcomes when compared to the placebo, the combination with THC notably reduced the anxiety-related subjective effects. Also, the mixture of 30 mg THC and 15 mg d-limonene significantly reduced feelings of anxiety and paranoia when compared to the administration of 30 mg THC alone. This anxiolytic effect did not extend to other pharmacodynamic effects, and the presence of d-limonene did not alter the pharmacokinetics of THC, indicating a specific interaction mechanism that merits further investigation.

Overall, the findings of this research indicates that d-limonene could play a pivotal role to enhance the therapeutic applications of THC by reducing its anxiogenic side effects. The implications of these outcomes strongly suggest that the entourage effect through which the constituents of cannabis interact in complex ways, does hold a significant potential for developing more precise and effective cannabis-based treatments. Further research is imperative to explore the impact of d-limonene in oral dose formulations and to investigate how other terpenoids and cannabinoids found in the cannabis might interact with THC to influence its pharmacological effects. 

Source:

Spindle, T. R., Zamarripa, C. A., Russo, E., Pollak, L., Bigelow, G., Ward, A. M., Tompson, B., Sempio, C., Shokati, T., Klawitter, J., Christians, U., & Vandrey, R. (2024). Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis. In Drug and Alcohol Dependence (Vol. 257, p. 111267). Elsevier BV. https://doi.org/10.1016/j.drugalcdep.2024.111267