Medical Research Terpenes (general)

Terpenes, Penetration Enhancers, and Pain

Written by Derek Johnson

Pain management paradigms in the healthcare industry have had serious problems delivering safe solutions. The opioid crisis is proof of this. In this universe of ruined lives, the very medicine dispensed to deal with pain creates a world of suffering of its own.

Fortunately, explorations into safer forms of pain relief are ongoing, and cannabis may just prove to be a source of sustainable, healthy, and effective relief from suffering.

Much study has been done on cannabinoids and pain. However, there are other potent compounds within Cannabis sativa that could potentially be pain relievers —terpenes are one such class of compounds. In a single C. sativa plant, you can find hundreds of mono- and sesquiterpenes, many of which are responsible for the smells and tastes of the plant’s flowers. Terpenes are present throughout nature, and are found in countless plants.

These compounds have been shown to have powerful health benefits, including anticancer and anti-inflammatory effects. They’ve also been shown to be antimicrobial.

Limonene and linalool are two terpenes that are often widely available in cannabis plants. Both have been shown to effective anxiolytics and sedatives [1,2] and both have been implicated as effective penetration enhancers. [3,4]

A penetration enhancer effectively increases the intake of another substance or substances when administered at the same time. In the right combination, a penetration enhancer can improve dosing efficiency by multiple percentage points.

This translates into lower dosages of problem pain drugs, such as opioid-based medication. Patients taking pain medication with lower dosages of problematic drugs face a far lower risk of addiction.

Linalool has proven to be an effective penetration enhancer when used with barbiturates administered to cause sleep. [5] Bisabolol has also been used as a penetration enhancer. This colorless terpenoid with a sweet aroma soothes and relaxes. It is also found in chamomile tea, a natural relaxant. Bisabolol has been used with propranolol hydrochloride to increase its skin permeance. [6]

Despite preclinical studies in animal models that have produced significant evidence of their analgesic properties, there is no direct evidence, yet, that terpenes by themselves can effectively control pain in humans. [7] The studies that have been done have considered essential oils like citrus, lavender, and rose oils that do contain abundant terpenes, but also many other chemicals. One such study found that β-caryophyllene reduced pain perception in mice by activating CB2 receptors. [8] In-depth investigation in humans via clinical trials, however, is definitely needed.

What we do know is that terpenes have been used safely for hundreds of years in cosmetic products and foods. They’re generally recognized as safe. They’re ubiquitous in nature. And they hold powerful health benefits, which likely includes pain relief, as scientific research will likely confirm in humans in time.

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[1] Linck VM, da Silva AL, Figueiró M, Caramão EB, Moreno PR, Elisabetsky E. Effects of inhaled linalool in anxiety, social interaction and aggressive behavior in mice. Phytomedicine. 2010;17(8-9):679-683. [journal impact factor = 5.34; times cited = 184]


[2] Komiya M, Takeuchi T, Harada E. Lemon oil vapor causes an anti-stress effect via modulating the 5-HT and DA activities in mice. Behav Brain Res. 2006;172(2):240-249. [journal impact factor = 3.332; times cited = 187]


[3] Vaddi HK, Ho PC, Chan SY. Terpenes in propylene glycol as skin-penetration enhancers: permeation and partition of haloperidol, Fourier transform infrared spectroscopy, and differential scanning calorimetry. J Pharm Sci. 2002;91(7):1639-1651. [journal impact factor = 3.534; times cited = 149]


[4] Chen J, Jiang QD, Chai YP, Zhang H, Peng P, Yang XX. Natural terpenes as penetration enhancers for transdermal drug delivery. Molecules. 2016;21(12):1709. [journal impact factor = 4.411; times cited = 68]


[5] Linck VM, da Silva AL, Figueiró M, et al. Inhaled linalool-induced sedation in mice. Phytomedicine. 2009;16(4):303-307. [journal impact factor = 5.34; times cited = 161]


[6] Cui Y, Li L, Zhang L, et al. Enhancement and mechanism of transdermal absorption of terpene-induced propranolol hydrochloride. Arch Pharm Res. 2011;34(9):1477-1485. [journal impact factor = 3.483; times cited = 25]


[7] Liktor-Busa E, Keresztes A, LaVigne J, Streicher JM, Largent-Milnes TM. Analgesic potential of terpenes derived from Cannabis sativa. Pharmacol Rev. 2021;73(4):98-126. [journal impact factor = 25.47; times cited = 0]


[8] Katsuyama S, Mizoguchi H, Kuwahata H, et al. Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception. Eur J Pain. 2013;17(5):664-675. [journal impact factor = 3.934; times cited = 100]

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Derek Johnson

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