# Therapeutic and Mechanistic Evaluation of Cannabis sativa Terpenes in Neuropathic Pain

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $320,759

## Abstract

ABSTRACT
 Chronic pain is a serious and worsening epidemic in the United States and worldwide, seriously
degrading patient quality of life. Opioid drugs like morphine are the “gold standard” for treating moderate to
severe chronic pain, however, they are burdened by major side effects, especially addiction liability, which has
contributed to a paralell epidemic of opioid addiction, abuse, and overdose. In addition, opioids are ineffective in
some pain types, most notably neuropathic pain. In the search for alternatives, phytocannabinoids from Cannabis
sativa have been heavily studied. However, cannabinoids have generally been shown to have modest to poor
efficacy, and have their own side effects, especially psychoactive side effects with Δ9-tetrahydrocannabinol
treatment. This has led again to a search for methods to improve cannabinoid therapy. For this reason, research
has focused on the ~150 terpene compounds found in Cannabis, which impart flavor and aroma to the plant.
Limited evidence suggests that terpenes produce pain relief on their own, and they have also been proposed to
modulate and potentially improve the effects of cannabinoids like THC, termed the “entourage effect” hypothesis.
However the quality of evidence on terpene efficacy is in general poor, limited by poorly-defined and complex
extracts, and few mechanistic studies. We thus performed a preliminary study on the Cannabis terpenes α-
humulene, β-pinene, geraniol, and linalool. We found that all 4 terpenes produced anti-nociception in a
mouse model of chemotherapy-induced peripheral neuropathy (CIPN) comparable or better than
morphine. At the same time, geraniol and linalool produced no reward or aversion, suggesting no addictive
or aversive liability. Seeking mechanistic insight, we found that all 4 terpenes produced tail flick anti-
nociception by a cannabinoid receptor type 1 (CB1) mechanism, and further synergized with the
cannabinoid WIN55,212, providing evidence for the entourage effect hypothesis. We further identified CB2,
Adenosine A2a, and anti-inflammatory activity as potential mechanisms of action. In this proposal, we will
extend these studies to evaluate therapeutic potential and mechanisms of action of these terpenes in neuropathic
pain, providing potential support to the use of these ligands as improved non-opioid pain therapeutics. In Aim 1,
we will fully test the terpenes in a mouse model of CIPN, including dose/response, alternate neuropathy models,
side effects like tolerance and reward/aversion, synergy with other analgesics such as opioids and cannabinoids,
and terpene impact on side effects of these other analgesics (especially opioid reward). In Aim 2, we will identify
molecular mechanisms for terpene action in CIPN, focusing on 1) CB1/2, 2) A2a, and 3) anti-inflammatory
activity. We will use selective antagonists and CRISPR gene editing, identify sites of action (e.g. brain, spinal
cord, periphery), measure tissue response to terpene (e.g. cytokine prod...

## Key facts

- **NIH application ID:** 10271680
- **Project number:** 1R01AT011517-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** John Michael Streicher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $320,759
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271680

## Citation

> US National Institutes of Health, RePORTER application 10271680, Therapeutic and Mechanistic Evaluation of Cannabis sativa Terpenes in Neuropathic Pain (1R01AT011517-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10271680. Licensed CC0.

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