Acetyl-L-carnitine (ALC), an acetyl ester of L-carnitine, present in both central and peripheral nervous systems, plays an important role in the oxidation of free fatty acids as well as in the intermediary metabolism ^[1][2][29,30]. Dietary supplementation of ALC exerts neuroprotective, neurotrophic, anti-depressive and analgesic effects in some painful neuropathies in animal models ^[3][4][5][31,32,33]. Furthermore, repeated ALC administration has been proven to promote regeneration of the injured nerves, increasing axon regeneration at the transected sciatic nerve stump, and restoring motor functions ^[1][6][29,34]. It has been proven to be effective in reducing pain in diabetes-related neuropathies, where it also seems to be capable of improving electromyography (EMG) parameters ^[5][7][8][33,35,36]. Pain reduction is probably caused by both a neuroprotective and a central anti-nociceptive mechanism of ALC ^[5][33].

Data regarding the effects of oral administration of ALC in Chemotherapy-induced peripheral neuropathy (CIPN) is inconclusive, with some studies proving its ability to prevent and/or treat CIPN, while others not only prove its ineffectiveness but suggest that it might exacerbate this condition ^[2][8][9][30,36,37]. In the study conducted by Pisano et al. ^[10][38], focused on the animal model of cisplatin- and paclitaxel-induced neuropathy, ALC co-treatment significantly reduced the severity of sensory loss and potentiated the levels of nerve growth factor (NGF), a neuroprotective agent, thus resulting in significantly reduced severity of neuropathy ^[10][38]. Furthermore, Flatters et al. ^[1][29] have proven ALC to prevent the onset of significant, paclitaxel-related pain up to three weeks after administration of the last dose of ALC ^[1][29]. Moreover, and possibly most importantly, ALC was proven to have no effects on the antitumour activity of the cytostatic drugs ^[10][11][38,39].

Observations made by Ghirardi et al. ^[11][39] were consistent with those mentioned above. They argue that the co-administration of ALC was able to prevent the oxaliplatin-related neurotoxicity, assessed using both behavioural and neurophysiological methods. Moreover, it was capable of reversing some neurological damage in the follow-up period after the end of the oxaliplatin therapy ^[11][39].

Nevertheless, observations made in the clinical trials were not consistent. While Bianchi et al. ^[12][40] observed a significant reduction in the symptoms of CIPN, a study performed by Hershman et al. ^[9][37] noticed in the double-blind trial that ALC supplementation was not only ineffective in the prevention of taxane-induced neuropathy in women undergoing breast cancer therapy, but also at 24 weeks of ALC therapy an exacerbation of CIPN was observed. Interestingly, the reason behind that vastly different result is not clear ^[9][11][37,39].

Although ALC was somewhat capable of attenuating established mechanical hypersensitivity caused by paclitaxel and cisplatin, its efficacy as a treatment option for CIPN is disputable and inefficient in comparison to its ability to prevent the development of painful neuropathy in the first place. As mentioned previously, no study observed an increase in the incidence rate of the CIPN caused by ALC administration, while this drug might potentially result in the exacerbation of the symptoms of the CIPN ^[1][11][29,39].

All vitamins from the B group, consisting of thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), cobalamin (B12), folate, choline, and biotin function as coenzymes in several intermediary metabolic pathways, including neurotransmitter synthesis and neuronal membrane synthesis ^[13][41]. Deficiency of vitamins from B group, especially B12, is known to cause neuropathies, usually accompanied by paraesthesia, numbness, and ataxia ^[14][15][16][42,43,44]. Observations regarding malignancy caused by B12 deficiency are in the line with the previous statement ^[17][45]. The most important factor differentiating cancer-caused deficiency from the “normal” deficiency, is the time frame. The clinically manifested significant decrease in cobalamin intake might take from 5 to 10 years, whereas the levels of vitamin B12 in some cancer affected patients have been proven to decrease rapidly, especially during chemotherapy, and the clinical manifestations are visible already after a few months ^{[17][18][19][20][21]}[45,46,47,48,49]. Schloss et al. ^[13][41] reported that vitamin B complex supplementation was statistically ineffective at preventing CIPN as compared to the placebo, although as indicated by the results of the Patient Neurotoxicity Questionnaire (PNQ), patients taking the vitamin B complex perceived a reduction in sensory peripheral neuropathy ^[13][41]. Importantly, in cases of CIPN coexisting with vitamin B12 deficiency, patients did benefit from the oral supplementation of this medication ^[13][20][41,48]. Lastly, Abe et al. ^[22][50] reported that oral vitamin B12 supplementation did not help in the prevention of the CIPN onset. Their study did not include the control group and they compared the efficacy of B12 supplementation versus goshajinkigan—observed incidence of neuropathy was 88.9% and 39.3%, respectively ^[22][50].

Vitamin E is often regarded as a treatment option for several neuropathies, such as diabetic neuropathy ^[23][24][25][52,53,54]. Furthermore, it is considered a useful agent for alleviating the symptoms of other chemotherapy-related toxicities ^[26][55]. Vitamin E is proven to be a strong antioxidant capable of protecting the integrity of cellular membranes from oxidative stress; hence, it might be potentially capable to prevent the free radicals caused nerve damage ^{[25][27][28][29]}[54,56,57,58]. Furthermore, although infrequent in clinical practice, vitamin E deficiency can be caused by an array of possible conditions including various cancers, such as acute lymphoblastic leukaemia, as well as treatment with chemotherapeutics, and cisplatin in particular ^{[30][31][32][33][34][35]}[59,60,61,62,63,64]. Importantly, some chemotherapeutics, such as cisplatin and oxaliplatin, exhibit oxidative traits. In the case of oxaliplatin, this ability is proven to be linked to the pathogenesis of CIPN ^[36][37][38][65,66,67]. Should the observations be applied to CIPN caused by other types of chemotherapy, vitamin E could constitute a potentially excellent treatment option in this type of peripheral neuropathy.

Although the majority of data regarding the feasibility of using vitamin E as a treatment option is consistent, some significant discrepancies can be observed. Pace et al. (2003) ^[39][68] in a study focused on patients diagnosed with a variety of cancers and treated with cisplatin, discovered a positive impact of vitamin E on the incidence and severity of CIPN. Here, the incidence of neurotoxicity was significantly lower in the group simultaneously treated with vitamin E (30.7%) than it was in the group receiving placebo (85.7%). Furthermore, when measured with a comprehensive neurotoxicity score based on clinical and neurophysiological parameters (a modified neurological symptom score, grading the severity of neuropathy as 1 = mild, 2 = moderate, and more than 2 = severe), the severity of polyneuropathy was also lower in the former group—2 vs. 4.7 respectively ^[40][69]. This observation was further confirmed by several other studies conducted by: Argyriou (2005) et al. ^[40][69], Argyriou et al. ^[41][70], and Argyriou et al. ^[42][71], who all share the same observations of considerably lower incidence of CIPN in vitamin E receiving group vs. placebo group—25% vs. 73.3% ^[40][69], 21.4% vs. 68.5% ^[41][70] and 18.7% vs. 62.5% ^[42][71] respectively. The same correlation was observed in regard to the severity of CIPN, all three studies measured it with the application of the modified peripheral neuropathy (PNP) score, observing a difference between the vitamin E-receiving group and the placebo group with the results of 3.4 ± 6.3 vs. 11.5 ± 10.6 ^[40][69], 4.99 ± 1.33 vs. 10.47 ± 10.62 ^[41][70] and 2.25 ± 5.1 vs. 11 ± 11.63 ^[42][71] respectively. Pace et al. (2010) ^[43][72] continued to advocate for the use of vitamin E as a potential medication in CIPN. Their observations were consistent with all the aforementioned studies and confirmed that a group of patients treated with vitamin E exhibited lower incidence (5.9%) of CIPN as compared to a placebo group (41.7%) The severity of neurotoxicity measured with the total neuropathy score (TNS; ranging from 0 to 40, higher values indicate more severe course of neuropathy) also indicated ameliorative capabilities of vitamin E, with a mean TNS of 1.4 vs. 4.1 in vitamin E and placebo groups, respectively ^[43][72]. Lastly, Agnes et al. ^[44][73] observed vitamin E to prevent mechanical and cold allodynia caused by oxaliplatin ^[44][73].

Regardless of all the above-mentioned observations, current data is not entirely conclusive. Studies conducted by Afonseca et al. ^[45][74] and Salehi et al. ^[46][75] indicated no positive effects resulting from vitamin E administration as a preventive agent, with this discrepancy potentially resulting from different chemotherapeutics reviewed in other clinical trials or the application of different scales ^[45][46][74,75]. Furthermore, the study led by Kottshade et al. ^[47][76] observed that vitamin E administration did not impact the incidence rate of CIPN significantly, although as pointed out by Miao et al. ^[48][77] in their excellent meta-analysis regarding this topic, the methodology of a Kottschade et al. ^[47][76] study remains disputable, therefore any conclusions should be made with special care ^[46][48][75,77]. Another study conducted by Heiba et al. ^[49][78] further displays the discrepancies between particular studies. Their clinical study indicated that vitamin E supplementation neither decreased the incidence of grade 2 or above neuropathy, nor the neuropathy onset time, yet the duration of the neuropathy was clearly different depending on the placebo group and vitamin E group, 12.5 weeks vs. 5 weeks, respectively ^[49][78].

It is important to remember that even though vitamin E supplementation can be indicated to be an effective way of preventing CIPN, such treatment is not entirely safe. A prospective, multicentre clinical trial involving 35,533 men observed a 17% increased risk of developing prostate cancer after a long-time vitamin E supplementation, thus, in males, the risks of such therapy might outweigh the potential gain ^[50][79].

Since ancient times, medicinal plants and herbs were used to ameliorate symptoms of a wide variety of different diseases and symptoms, including pain of different kinds, and neurological conditions ^{[51][52][53][54]}[80,81,82,83]. It is believed that there is a strong rationale for this kind of medication, thus a more detailed review of its medical potential in CIPN treatment can be advised.