Goshajinkigan (GJG) is a traditional Japanese medicine (Kampo) composed of ten herbs (Rehmanniae, Achyranthis Radix, Corni Fructus, Dioscoreae Rhizoma, Plantaginis Semen, Alismatis Rhizoma, Poria, Moutan Cortex, Cinnamomi Cortex, and Processi Aconiti Radix) mixed in a fixed proportion [84,85,86]. In Japan, GJG is often prescribed as a treatment option used to alleviate the symptoms of diabetic peripheral neuropathy i.e., numbness, cold sensations, and paraesthesia/dysesthesia [87,88,89,90].

An animal study conducted by Mizuno et al. [91] decided to focus on the TRP channels including Ca2⁺-permeable nonselective cation channels suggested to serve as thermal, chemical, and mechanical sensors, with a particular focus on TRPA1 and TRPM8 [92,93,94,95,96]. As observed in the real-time polymerase chain reaction (rtPCR), oxaliplatin increased the expression levels of TRPA1 and TRPM8 mRNA resulting in hypersensitivity to cold, while GJG administration prevented that increase [92]. Another animal study was performed by Ushio et al. [97], where the authors discovered that GJG was capable of preventing oxaliplatin-related cold hyperalgesia, although it had no effect on oxaliplatin-related allodynia. Importantly, the authors discovered that GJG had no negative effect on oxaliplatin-induced tumour cytotoxicity [97].

Nishioka et al. [98] sought to investigate the possibility of using GJG as a preventive option for CIPN. A group of patients diagnosed with colorectal cancer treated with a modified FOLFOX6 regime, containing oxaliplatin, was divided into two subgroups, with one subgroup receiving oral administration of GJG every day, and the other receiving placebo. Neuropathy was assessed using the Neurotoxicity Criteria of Debiopharm (DEB-NTC) during every course. Their study claimed that the incidence of grade 3 peripheral neuropathy in the GJG group was significantly lower than in the control group, and after 10 courses of chemotherapy, there were no cases of adverse effects in the study group (0%), while in the placebo-receiving group this number reached 12% (p < 0.01) [98]. These observations were further confirmed in the subsequent studies. Kono et al. [87,99] focused on a similar group of patients diagnosed with colorectal cancer and treated with FOLFOX regime and subdivided similarly to the previous study. Consistently with the research of Nishioka et al., Kono et al. [99] found GJG to both decrease the incidence rates of the CIPN, as measured with DEB-NTC, and ameliorate its effects [100]. Kono et al. later [87] used a different scale, Common Terminology Criteria for Adverse Events (CTC-AE), but the results remained consistent with the previous ones. Here, the incidence rate of grade 2 or greater CIPN, until the 8th cycle of chemotherapy, was 39% in the GJG group and 51% in the placebo group, with the incidence rate of grade 3 CIPN being 7% in the GJG group vs. 13% in the placebo group [87]. The last study focused on the FOLFOX6 treated group of patients diagnosed with colorectal cancer was the one performed by Oki et al. [100] The patient division introduced in the study, was similar to the division presented in the previous two studies. Importantly, this study contradicted the first two, where authors, using the scale of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC) to assess neuropathy, observed that GJG not only did not prevent CIPN, but it might have had a contrary effect. The incidence of grade 2 or greater neurotoxicity was 50.6% and 31.2% in the GJG and the placebo group respectively [100]. The reason for this difference remains unclear, although it might be attributed to the differences in the methodology applied in these studies. Nevertheless, this question remains yet to be answered.

Studies performed by Abe et al. [50] and Kawabata et al. [101] decided to focus on a different approach, with the main focus being the efficacy of GJG in breast cancer patients suffering from CIPN and treated with docetaxel (in the case of Abe et al.) or paclitaxel (in a case of Kawabata et al.) [50,101]. Abe et al. [50] compared the efficacy of B12 supplementation to GJG supplementation with neuropathy being evaluated according to DEB-NTC, NCI-CTC ver. 3.0, and a visual analogue scale (VAS). The authors observed an incidence of neuropathy of 39.3% in the GJG group and 88.9% in the B12 group, with a significantly lower incidence rate of adverse events in the former group [50]. Kawabata et al. [101] measured the difference in the reduction of CIPN with several questionnaires, as well as CTC-AE v4.0, and their results contradicted some of the previous studies. Here, all patients experienced CIPN of either hands or feet at 4 weeks of study and the entire GJG group experienced CIPN of both hands and feet at 12 weeks, while in the control group only 2 out of 6 patients experienced such condition at this time frame [101]. Nevertheless, it is important to mention the differences between the two studies. Abe at al. [50] study included no control group, while the group of patients being reviewed in the Kawabata et al. [101] study was small, with the GJG group consisting of only 4 patients. Furthermore, both studies used different methods of evaluating the severity of CIPN. The discrepancy in the results between these two studies might be caused by either those factors or a sum of all of them.

Citrullus colocynthis, also known as bitter apple, is a plant used in traditional medicine as an anti-inflammatory, antidiabetic, analgesic, hair growth-promoting, abortifacient, and antiepileptic compound with disputable results [109,110,111,112]. In Rostami et al. study focusing on patients diagnosed with CIPN, the effects of treatment with C. colocynthis extract oil were evaluated in the randomized, double-blind, placebo-controlled clinical trial. Unfortunately, C. colocynthis extract oil did not ameliorate the symptoms of CIPN [113].

Matricaria chamomilla L. extract contains terpenoids like α-bisabolol and its oxide azulenes, including chamazulene and acetylene derivatives and flavonoids: apigenin, luteolin or others [114]. Apigenin was reported to have antioxidative effects, resulting in neuroprotective effects against oxidative stress in neurological disorders [110,115]. Moreover, apigenin treatment by modulating levels of cytokines and nitric oxide can be protective for neurites and cell viability against inflammation [116,117,118]. In mice models of cisplatin-induced neuropathy, M. chamomilla was able to decrease pain and inflammation which was measured in the formalin test [119]. To the best of authors’ knowledge, no clinical trials investigating the feasibility of using M. chamomilla as an ameliorative factor in CIPN have been performed to this day.

Salvia officinalis, which contains phenolic acid and flavonoid content, has anti-inflammatory and antioxidant effects on lipopolysaccharide-induced inflammation as shown in the mice model. The Salvia officinalis administration resulted in a decrease of inflammatory markers, which, according to the authors’ suggestion, might be caused by the inhibition of reactive lipid peroxidation or/and the consumption of antioxidants by scavenging reactive oxygen radicals [120]. This plant can be also useful in the enhancement of cognitive activity and protection against neurodegenerative diseases [121]. In Alzheimer’s Disease, S. officinalis improved cognitive functions with no side effects compared to the placebo group [122,123]. The influence of S. officinalis on CIPN has been shown in a mice model, where its extract increased vincristine-induced pain response [124].

Cinnamomum cassia, which contains coumarins, cinnamic acid, as well as cinnamaldehyde, was described as a neuroinflammation-inhibiting compound, capable of exerting its action through attenuation of iNOS, COX-2 expression and NF-κB [125]. The study by Kim et al. [126] presented that the administration of Cinnamomum Cortex (the bark of C. cassia) water extract could induce a significant suppression of the activation of astrocytes and microglia. After cold allodynia causing oxaliplatin injection, C. Cortex water extract has been observed to decrease the expression levels of IL-1β and TNF in the spinal cord. Moreover, the same study showed that coumarins, the compound of C. Cortex, can attenuate oxaliplatin-induced cold allodynia in rats [126].

Curcumin is a commonly known substance, which positively impacts health by decreasing the risk for several pathologies: cardiovascular diseases [127], type 2 diabetes mellitus [128], cancer [129], but also against neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis among others [130]. Recent studies have shown that curcumin, with its poor water solubility, cannot act directly on the central nervous system, rather affecting the “microbiota-gut-brain axis”, so that the functions of the brain are preserved [131]. Curcumin, due to its influence on NF-ĸB [132], COX-2 and pro-inflammatory cytokines [133], is also described as an anti-inflammatory, antioxidant, and neuroprotective substance [134]. Curcumin, in the mice model, decreases vincristine-induced neuropathic pain including hyperalgesia and allodynia. Additionally, an antioxidative effect has been observed in the curcumin-treated group [135]. Agthong et al. [136] noticed that curcumin prevented thermal hyperalgesia in rats with cisplatin-induced neuropathy. Moreover, in this study morphometric analysis of L4 dorsal root ganglia was performed, and in the curcumin-treated group less pathological changes, such as nuclear or nucleolar atrophies including the loss of neurons, have been observed [137]. As mentioned previously, one of the pathomechanisms of cisplatin-related neuropathy is oxidative stress caused by this chemotherapeutic.