**1. Introduction**

Neuropathic pain is a condition that is caused by damage to the nervous system as a result of physical trauma, chemotherapy, infection, metabolic disease, or autoimmune disorders [1,2]. This chronic pain condition affects 7–10% of the population and, unfortunately, current drug treatments have poor efficacy and tolerability [3,4]. Patients are typically unresponsive to analgesics and opioids. In addition to pain, patients also suffer from sleep disturbances, anxiety and depression, and reduced quality of life [5]. The incidence of neuropathic pain is expected to increase in the coming years due in part to the diabetes epidemic, improved cancer survival rates, and age [6]. Therefore, new approaches to treat pain in these patients are clearly needed.

Cannabis has been used for centuries to treat pain, and the plant contains a number of pharmacologically active compounds including cannabinoids and terpenes that might have anti-nociceptive properties [7,8]. The two most abundant and studied cannabinoids in the plant are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and the ratio of these two compounds can vary greatly between cultivars and subtypes of *Cannabis*. Both THC and CBD have been shown to reduce neuropathic pain in animal models [9–13]. However, patients rarely take pure THC or CBD for pain. Additionally, THC and CBD are normally administered together at varying ratios depending on the product consumed. Furthermore, the anti-nociceptive effects of these varying ratios of THC and CBD remain underexplored. Instead, studies have largely focused on THC:CBD co-administered at 1:1 ratios, commonly found in the European-approved Sativex (nabiximols) that has been shown to be effective at treating pain in patients with certain conditions [14–17]. We

**Citation:** Sepulveda, D.E.; Vrana, K.E.; Graziane, N.M.; Raup-Konsavage, W.M. Combinations of Cannabidiol and Δ9-Tetrahydrocannabinol in Reducing Chemotherapeutic Induced Neuropathic Pain. *Biomedicines* **2022**, *10*, 2548. https://doi.org/10.3390/ biomedicines10102548

Academic Editor: Giuseppe Tringali

Received: 1 September 2022 Accepted: 10 October 2022 Published: 12 October 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Hershey, PA 17033, USA

therefore set out to assess how different combinations of THC and CBD, as both pure compounds and from unfractionated plant extracts, affect mechanical hypersensitivity in a mouse model of chemotherapeutic-induced peripheral neuropathy (CIPN).

#### **2. Materials and Methods**
