Rev. Neurosci.
2019; aop
Farnaz Ebrahimi, Mohammad Hosein Farzaei, Roodabeh Bahramsoltani, Mojtaba Heydari,
Kiana Naderinia and Roja Rahimi*
Plant-derived medicines for neuropathies:
a comprehensive review of clinical evidence
https://doi.org/10.1515/revneuro-2018-0097
Received September 19, 2018; accepted November 5, 2018
Abstract: Neuropathy is defined as the damage to the
peripheral or central nervous system accompanied by
pain, numbness, or muscle weakness, which can be due to
congenital diseases or environmental factors such as dia-
betes, trauma, or viral infections. As current treatments are
not sufficiently able to control the disease, studies focus-
ing on the identification and discovery of new therapeutic
agents are necessary. Natural products have been used for
a long time for the management of different neurological
problems including neuropathies. The aim of the present
study is to review the current clinical data on the benefi-
cial effects of medicinal plants in neuropathy. Electronic
databases including PubMed, Scopus, and Cochrane
Library were searched with the keywords ‘neuropathy’ in
the title/abstract and ‘plant’ or ‘extract’ or ‘herb’ in the
whole text from inception until August 2017. From a total
of 3679 papers, 22 studies were finally included. Medicinal
plants were evaluated clinically in several types of neu-
ropathy, including diabetic neuropathy, chemotherapy-
induced peripheral neuropathy, carpal tunnel syndrome,
*Corresponding author: Roja Rahimi, Department of Traditional
Pharmacy, School of Persian Medicine, Tehran University of Medical
Sciences, Tehran 14167-53955, Iran, e-mail: rojarahimi@gmail.com
Farnaz Ebrahimi: Pharmacy Student’s Research Committee,
School of Pharmacy, Isfahan University of Medical Sciences, Isfahan
84156-83111, Iran; and PhytoPharmacology Interest Group (PPIG),
Universal Scientific Education and Research Network (USERN),
Isfahan 84156-83111, Iran
Mohammad Hosein Farzaei: Medical Biology Research Center,
Kermanshah University of Medical Sciences, Kermanshah 67158-
47141, Iran; and Pharmaceutical Sciences Research Center,
Kermanshah University of Medical Sciences, Kermanshah 67158-
47141, Iran
Roodabeh Bahramsoltani: Department of Traditional Pharmacy,
School of Persian Medicine, Tehran University of Medical Sciences,
Tehran 14167-53955, Iran
Mojtaba Heydari: Research Center for Traditional Medicine and
History of Medicine, Shiraz University of Medical Sciences,
Shiraz 71348-14336, Iran
Kiana Naderinia: Department of Food and Drug Analysis, School
of Pharmacy, Ahvaz Jundishapur University of Medical Sciences,
Ahvaz 61357-15794, Iran
and HIV-associated neuropathy. Some studies reported the
improvement in pain, nerve function, nerve conduction
velocity, and quality of life. Cannabis sativa (hemp), Linum
usitatissimum (linseed oil), capsaicin, and a polyherbal
Japanese formulation called Goshajinkigan had the most
evidence regarding their clinical efficacy. Other investi-
gated herbal medicines in neuropathy, such as Matricaria
chamomilla (chamomile), Curcuma longa (turmeric), and
Citrullus colocynthis (colocynth), had only one clinical
trial. Thus, future studies are necessary to confirm the
safety and efficacy of such natural medicines as a comple-
mentary or alternative treatment for neuropathy.
Keywords: herbal medicine; medicinal plant; neuropathy;
pain; traditional medicine.
Introduction
Neuropathy is a type of neurological disease that can be
caused by functional damage to sensory nerves that are
responsible for peripheral sensation, motor nerves that
carry the signals for muscle contraction, or the autonomic
nervous system that controls involuntary body functions
(Misery et al., 2014).
Neuropathy symptoms are different depending on
the location of damaged and affected nerves and can be
accompanied by symptoms such as burning sensation and
itching (Misery et  al., 2014), numbness, pain, or muscle
weakness in the extremities, which can cause problems
such as inability to stand, walk, or hold objects for a long
time (Andersen, 2014).
Several factors including congenital disorders
(Grunewald et al., 2002), infections (Al-Saffar and Al-Fatly,
2018), diabetes mellitus (Singh et al., 2014), severe malnu-
trition, environmental toxicants (Rao et  al., 2014), drugs
(Shetty and Shah, 2018), and mechanical nerve injuries
are involved in the pathophysiology of neuropathic pain.
According to pathophysiology and etiology, neuropa-
thies are classified into several types including diabetic
neuropathy, neuropathy due to viral infections, alcohol-
induced neuropathy, hereditary neuropathy, or neuropa-
thy due to autoimmune diseases. It is also classified as
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM
2      F. Ebrahimi et al.: Herbal medicines for neuropathies
mononeuropathy and polyneuropathy according to the
number of affected nerves.
Neuropathy is one of the prevalent causes of pain
(Colloca et  al., 2017). A study on patients with chronic
back pain showed that about 40% of the participants have
experienced some signs of neuropathy (Freynhagen et al.,
2006). The prevalence seems to be higher in women and
is increased with age. Lumbar and cervical painful radicu-
lopathies are the most common suspects of chronic neuro-
pathic pain (Colloca et al., 2017).
Most types of neuropathy do not have a specific treat-
ment and can only be prevented or alleviated by the treat-
ment of the baseline disease. In this case, symptomatic
treatment, especially pain management, seems to improve
the quality of life (QOL; Finnerup et  al., 2015). Current
available treatments include the administration of anal-
gesics, anticonvulsants, and antidepressants (Singh et al.,
2014). In some cases, physiotherapy and the use of aux-
iliary devices are also recommended (Sacco et al., 2017).
However, as most available medicines have several com-
plications such as weight gain, drowsiness, impotency,
and sleep disturbance (Ferguson, 2001), the investigation
for the discovery of new treatments is necessary.
Medicinal plants have a long history of use as comple-
mentary or alternative treatment options for the manage-
ment of different diseases, including chronic pain (Heydari
et al., 2015). Scientific evaluation of plants and their second-
ary metabolites has suggested beneficial effects of these
agents for the management of several neuropsychological
disorders (Farzaei et al., 2018), such as Parkinson’s disease
(Shahpiri et  al., 2016), multiple sclerosis (Farzaei et  al.,
2017), diabetic neuropathy (Grover et al., 2002), and cancer-
related pain (Farzaei et al., 2016). Phytochemicals such as
epigallocatechin-3-galate, curcumin, and resveratrol have
demonstrated anti-inflammatory effects in several studies
(Bahramsoltani et al., 2015). In some cases, medicinal plants
have fewer side effects and patients might be more willing
to use such treatment options; thus, medicinal plants could
attract the attention of scientists to be clinically investigated
as an adjuvant treatment for different types of neuropathic
pain. In this regard, the aim of this study is to review the
clinical evidence on the effectiveness of herbal medicines
including medicinal plants and their secondary metabolites
as well as multicomponent herbal preparations for the man-
agement of neuropathic pain with different origins.
Search strategy
Electronic databases including PubMed, Scopus, and
Cochrane Library were searched until August 2017  with
the following formula: Neuropathy[title/abstract/key-
words] AND (plant OR extract OR herb) [all fields]. Clini-
cal trials assessing the effectiveness of an herbal product
including a medicinal plant, its secondary metabolite,
or a multicomponent herbal preparation in neuropathic
pain were included in this review. Only papers with
English full-text were included in our study. Studies on
other types of pain or nerve injuries unrelated to neurop-
athy, animal or cellular studies, and human studies other
than clinical trials were also excluded. Final included
articles were reviewed regarding the type of neuropathy,
evaluated medicinal plant(s), study design and duration,
outcomes, and side effects. Jadad score was applied for
the evaluation of the methodological quality of each trial
(Jadad et al., 1996).
Results
From a total of 3679 primarily retrieved papers, the final
number of 22  studies was included. Figure 1 shows the
flow diagram of the study selection process. Data obtained
from the final included papers are summarized in Table 1.
The results of the studies are discussed below based on
the investigated type of neuropathy.
Total number of papers: 3679
PubMed: 743
Cochrane: 72
Scopus: 2864
Primarily excluded papers: 3650
Excluded due to duplication: 462
Excluded because of being review: 26
Excluded based on title/ abstract: 3162
29 retrieved papers
Excluded based on full-text: 7
Evaluation of pharmacokinetics
without discussing the efficacy: 1
Focusing on complications other than
neuropathy: 6
22 final papers
Figure 1: Flow diagram of the study selection process.
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM
 Table 1: Clinical studies on the effectiveness of medicinal plants and herbal medicines in different types of neuropathy.

Plant/phytochemical   Dosage   Study design   Jadad  Concomitant therapy   Duration   Outcome   Reference
name score

C. sativa   3.56% THC   Randomized, placebo-controlled   4  Gabapentin, opioids   5 days   ↓Pain and total mood disturbance   Abrams et al.,
trial in 50 patients with HIV- 2007
associated sensory neuropathy
C. sativa   THC (27 mg/ml) or   Randomized, double-blind,   5  Analgesics   2 weeks   ↓Pain (BS-11) statistically but   Berman et al.,
Sativex (THC 27 mg/ml crossover, controlled trial not clinically significant, ↓sleep 2004
and CBD 25 mg/ml) in 48 patients with central quality and disturbance, ↓GHQ-
(maximum of eight puffs neuropathic pain from brachial 12 by THC:CBD but not by THC,
as oromucosal spray) plexus avulsion ↓SF-MPQ VAS by THC but not by
THC:CBD
C. sativa   Sativex (THC 27 mg/ml   Randomized, double-blind,   3  –   12 weeks   No significant change in DPS,   Selvarajah
and CBD 25 mg/ml) as placebo-controlled trial in TPS, EuroQOL, and SF-36, ↓TPS et al., 2010
oromucosal spray QID 30 patients with diabetic in a subgroup of patients with
neuropathy depression
C. sativa   2.7 mg THC and 2.5 mg   Randomized, double-blind,   3  Amitriptyline or other   5 weeks   ↓NRS-11 and NPS TPS and   Rog et al.,
CBD as oromucosal spray placebo-controlled, parallel- tricyclic antidepressants pain-related sleep disturbance, 2005
group trial in 66 patients with no differences between HADS
multiple sclerosis and central anxiety and depression and Guy’s
pain states Neurological Disability Scale and
PGIC were improved
Capsaicin   Patch of capsaicin with   Open-label pilot study in 12   –  Hydrocodone bitartrate/   12 weeks   ↓Average pain for the past 24 h,   Simpson et al.,
640 mg/cm2 (NGX-4010 patients with painful HIV- acetaminophen, oral worst pain for past 24 h, pain now 2008b
or control, a low- associated DSP analgesics including scores
concentration capsaicin anticonvulsants,
patch) applied for 30, opioids, and
60, or 90 min antidepressants
Capsaicin   Patch of capsaicin with   Randomized, double-blind   5  Hydrocodone bitartrate/   12 weeks   ↓Pain, worst pain for past 24 h,   Simpson et al.,
640 mg/cm2 (NGX-4010 study in 307 patients with HIV- acetaminophen and improvements in the Gracely Pain 2008a
or control, a low- associated DSP patients continued their Scale, SF-MPQ, BPI composite
concentration capsaicin stable chronic pain score, and PGIC and CGIC scores in
patch) applied for 30, medication regimens all three NGX-4010 dose groups
60, or 90 min
C. colocynthis   2 ml oil BD   Two-arm randomized, double-   5  –   3 months   ↑Mean pain score, NCV, CPN, SPN,   Heydari et al.,
blind, placebo-controlled significant improvement for mean 2016
clinical trial in 60 patients with score in the physical domain of
painful diabetic polyneuropathy WHOQOL-BREF

Download Date | 2/16/19 12:24 PM

Authenticated
Brought to you by | Lund University Libraries
F. Ebrahimi et al.: Herbal medicines for neuropathies      3
 Table 1 (continued)
Plant/phytochemical   Dosage   Study design  
name
C. longa   800 mg curcumin   Open, randomized, controlled  
phytosome, 4 mg clinical trial on 135 subjects
piperine with peripheral neuropathy
G. biloba   120 mg extract   Randomized, double-blind,  
placebo trial in 156 patients
with diabetic sensorimotor
polyneuropathy
GJG   2.5 g TDS   Randomized, open-label clinical   2  –
trial in 149 type 2 diabetic
patients
GJG   2.5 g TDS   Retrospective study in 73  
colorectal cancer patients with
oxaliplatin-induced peripheral
neuropathy
GJG   7.5 g   Randomized, controlled trial  
in 29 patients with ovarian
or endometrial cancer who
underwent chemotherapy
and developed peripheral
neuropathy
Guduchyadi Kwatha   80 mg daily   Randomized, open-label trial  
in 60 patients with diabetic
polyneuropathy
L. usitatissimum   Topical seed oil, five   Randomized, double-blind,  
drops of BD placebo-controlled clinical trial
in 155 patients with idiopathic
mild to moderate CTS
L. usitatissimum   Topical gel BD   Randomized, controlled trial  
in 49 patients with mild to
moderate idiopathic CTS
Download Date | 2/16/19 12:24 PM
Authenticated
Brought to you by | Lund University Libraries
Jadad  Concomitant therapy   Duration   Outcome   Reference
score
2  Statins, hypoglycemics,   8 weeks   ↓Neuropathic pain and duration of   Di pierro et al.,
Eutirox, ticlopidine, analgesic use 2013
warfarin, calcium
antagonists,
β-blockers, antibiotics,
gastroprotectants, and
the contraceptive pill
5  –   6 months   Improvement of sensory,   Numan et al.,
affective, VAS, and PPI scores in 2016
SF-MPQ, no significant effect on
electrophysiological parameters
  7 years   ↓Progression of ankle reflex   Watanabe
et al., 2014
–  FOLFOX6, XELOX   ≥4 weeks   ↓Deleterious effects in comparison  Yoshida et al.,
4      F. Ebrahimi et al.: Herbal medicines for neuropathies
to untreated patients 2013
2  Vitamin B12   6 weeks   ↓Frequency of abnormal CPT, no   Kaku et al.,
significant change in VAS, NCI- 2012
CTCAE neuropathy grade, FACT-
Taxane, and CPT ranges
1  Methylcobalamine and   3 months   Improvement in karapadadaha,   Parveen and
gabapentine karapadasupti, chumchumaya, Sarma, 2016
sign of vibration sensation,
monofilament test, daurbalya,
shola, and Toronto Clinical Score
5  –   4 weeks   ↓BCTQ SYMPT and FUNCT, MDL,   Hashempur
↑NCV, no significant differences in et al., 2015
MDL and SDL
2  –   3 weeks   Not significantly different in terms   Setayesh et al.,
severity of CTS, improvements of 2016
symptoms and function
 Table 1 (continued)

Plant/phytochemical   Dosage   Study design   Jadad  Concomitant therapy   Duration   Outcome   Reference
name score

M. chamomilla   10 drops of prescribed   Pilot, randomized, double-   5  –   4 weeks   ↓Severity of symptoms,   Hashempur
oils (topical) containing blind, placebo-controlled trial ↑functional status, no significant et al., 2015
2.05% chamazulene in 26 patients with documented effect on the electrodiagnostic
and 62.35% bisabolone severe CTS parameters
oxide
M. fragrans   Topical nutmeg oil 4 puff   Randomized, double-blind,   5  –   4 weeks   ↓Pain within group, but no   Motilal and
TDS placebo-controlled trial in significant difference in any Maharaj, 2013
74 with diabetic painful outcome between the two groups
neuropathy
Nabiximols (oral mucosal   Maximum 12 puffs per   Double-blind, placebo-   1  –   6 months   ↓Pain (NRS-PI)   Lynch et al.,
spray containing day controlled, crossover pilot trial 2014
cannabinoids) in 16 patients with CIPN pain
Neuragen PN polyherbal   Topical spray ~0.75 ml   Randomized, double-blind,   3  –   8 h   ↓Pain (VAS) in all patients and in a   Li, 2010
formula per foot per treatment placebo-controlled clinical trial subgroup of diabetic patients
in 60 patients with peripheral
neuropathy
Oenothera spp.   360 mg GLA   Randomized, double-blind,   3  –   6 months   ↓Symptom score, ankle HT, wrist   Jamal and
placebo-controlled study in 22 HT, ↑median MCV, peroneal MCV, Carmichael,
patients with distal diabetic median CMAP, peroneal CMAP, 1990
polyneuropathy median SNAP, sural SNAP
P. niruri + A. indicum   P. niruri 3 g + A. indicum   Clinical trial in 33 patients with   –  –   30 days   Improvement in perception of   Patel et al.,
decoction 10 g BD diabetic neuropathy vibration, heat, and cold sensation 2011
α-Lipoic acid + B.   α-Lipoic acid   Prospective study in 25 subjects   –  –   12 weeks   ↓Pain (VAS), sensory and motor   Desideri et al.,
serrata + MSM +  (240 mg) + B. serrata with CIPN neuropathic impairment (NCI- 2017
bromelain (40 mg) + MSM CTCAE score), TNSc, mISS
(200 mg) + bromelain
(20 mg)

BD, bis die (two times a day); CGIC, Clinician Global Impression of Change; CMAP, compound muscle action potential amplitude; CPN, common peroneal nerve; DPS, neuropathy total symptom
score; HT, heat threshold; MCV, median nerve motor conduction velocity; PGIC, Patient Global Impression of Change; PRN, as needed; QID, quater in die (four times a day); SNAP, sensory nerve
action potential; TDS, ter die sumendum (three times a day).

Download Date | 2/16/19 12:24 PM

Authenticated
Brought to you by | Lund University Libraries
F. Ebrahimi et al.: Herbal medicines for neuropathies      5
6      F. Ebrahimi et al.: Herbal medicines for neuropathies
Diabetic neuropathy
Diabetic neuropathy is one of the most investigated
types of neuropathy. It occurs in both types of diabetes
and results from the damage to the peripheral or central
nervous system. More than 50% of patients with diabe-
tes mellitus experience peripheral neuropathy and 10%
of them suffer from neuropathic pain, including hyper-
algesia, hyperesthesia, dysesthesia, paresthesia, and
allodynia, which all can affect their performance in daily
life (Watson et al., 2003). There is growing evidence that
this microvascular complication of diabetes is mediated
by oxidative stress due to the production of free radicals.
It is shown that diabetic neuropathy can be improved by
the supplementation with natural antioxidants in animal
models of diabetic neuropathy (Sharma et al., 2007).
Oenothera spp. (evening primrose) from the Ona-
graceae family is found in different parts of the world.
The oil, obtained from its grains, carries a large amount
of essential fatty acids, including γ-linolenic acid (GLA),
which has a significant role in the human body’s metab-
olism (Deng et  al., 2001). An in vivo study showed the
evening primrose oil to be able to repair myelin damage
and decrease endoneurial edema due to diabetic neu-
ropathy (Omran, 2012). In a double-blind, placebo-con-
trolled study, the effect of evening primrose oil on diabetic
neuropathy was investigated in 22 diabetic patients for
6  months. Results showed a significant improvement in
both subjective (heat threshold studies) and objective
(nerve conduction studies) outcome measures. No signifi-
cant change in mean HbA1c of treatment group in compar-
ison to the placebo group was observed. There was also
no significant relationship between the improvement of
nerve activity measurements and HbA1c in active group.
Therefore, it was concluded that evening primrose oil may
improve diabetic neuropathy and its effect is independent
to glycemic control. However, because of a short follow-
up period, this needs to be investigated in future studies
(Jamal and Carmichael, 1990).
Myristica fragrans Houtt (nutmeg), which is native
to West Africa, is a plant from Myristicaceae family. It
contains both volatile oil (5–15% of which constitutes
camphene, sabinene, pinene, isoeugenol, eugenol, isoe-
lemicin, elemicin, myristicin, lignans, dimeric phenylpro-
panoids, safrole, methoxyeugenol, and neolignans) and
fixed oil (Tajuddin et al., 2005). Myristicin has previously
demonstrated neuroprotective properties in hypoxia-
induced neural damage in rat dorsal root ganglion via
the regulation of apoptotic mediators such as caspase-3,
B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein, and
antioxidant activities (Zhao et  al., 2017). Allylguaiacol,
another ingredient of nutmeg, has also shown cytoprotec-
tive activity in hippocampal cells by several mechanisms,
including the elevation of brain-derived neurotrophic
factor (BDNF) and the modulation of the nuclear factor-
κB pathway (Lim et  al., 2018). In a double-blinded, ran-
domized, controlled trial, subjects with diabetes were
evaluated in two groups of 40 each, which received a
compound herbal topical formulation including 14%
nutmeg fixed oil or placebo. The Brief Pain Inventory (BPI)
for Diabetic Painful Neuropathy and Neuropathic Pain
Symptom Inventory was used to identify the quantitative
differences in neuropathic pain. There was a significant
reduction in the pain score and interference with function
(sleep, mood, and walking) in the nutmeg group in com-
parison to the baseline values and also the placebo group.
The prevalence of side effects was similar in both groups
(Motilal and Maharaj, 2013).
Ginkgo biloba L., known as living fossil, is the only
member of Ginkgoaceae family. The leaf extract con-
sists of a wide variety of flavonoids, including quercetin,
kaempferol, isohamnetin, and specific terpenes such
as ginkgolide and bilobalide. The plant is used in tradi-
tional medicines of different countries and is a potent free
radical scavenger (Mahady, 2001). Ginkgo extract could
significantly improve diabetic neuropathy in a rat model
via the reduction of lipid peroxidation and the elevation
of endogenous antioxidant defense mechanisms such as
superoxide dismutase (SOD) and catalase (CAT; Taliyan
and Sharma, 2012). The effect of a ginkgo preparation
was compared to placebo in patients with diabetic senso-
rimotor polyneuropathy. The efficacy of the intervention
was investigated by the Short-Form McGill Pain Question-
naire (SF-MPQ) and the electrophysiological parameters
of motor and sensory nerves. Statistical analysis showed
a significant improvement in sensory, visual analogue
score (VAS) and present pain intensity (PPI) as well as the
total scores of SF-MPQ. The supplement also improved
the latency of the motor ulnar nerve and the conduc-
tion velocity of the motor peroneal nerve. Dry mouth was
the most frequent side effect in ginkgo-treated groups
(Numan et al., 2016).
Phyllanthus niruri L. (from Phyllanthaceae), which
mainly grows in America, contains alkaloid, flavonoid,
terpene, tannin, phenol, coumarin, and a lignan called
phyllanthin (Khanna et al., 2002). The plant is suggested
to have neuroprotective properties due to its potent iron-
chelating activity (Lee et al., 2016). Abutilon indicum (L.)
Sweet is from Malvaceae family and can be found in dif-
ferent parts of the world. Its analgesic effects have been
demonstrated and are comparable to acetylsalicylic acid.
Components such as lauric acid, myristic acid, palmitic
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM

acid, stearic acid, oleic acid, linoleic acid, caprylic acid,
and capric acid exist in the oil. Gallic acid and vitamin
E can also be found in some parts of this plant (Matlaw-
ska and Sikorska, 2002). In a clinical study, the effect
of an oral herbal preparation containing P. niruri and A.
indicum was investigated on diabetic neuropathy. A total
of 33 patients were treated with a combination of the two
plants for 30 days. The vibration, heat, and cold sensation
threshold were evaluated by an electronic neuropathy
analyzer. The results showed that all symptoms includ-
ing numbness, tingling sensation, burning sensation, and
pain signs were significantly improved (Patel et al., 2011).
Cannabis sativa L. (hemp) is from Cannabaceae
family and now grows in all parts of the world. The main
components of the plant are cannabinoids, including tet-
rahydrocannabinol (THC) and cannabidiol (CBD), which
are responsible for the majority of biological activities
attributed to hemp (Andre et  al., 2016). In an animal
model of diabetic neuropathy, cannabis extract could
significantly restore the oxidative damage of the neurons
and elevate the level of nerve growth factor, which shows
the improvement of neurotrophin support (Comelli et al.,
2009). Another animal study has suggested transient
receptor potential vanilloid 1 (TRPV1) channel (trans-
membrane channels involved in the nociception) to
participate in the analgesic effects of cannabis (Comelli
et al., 2008). CBD seems to act via the reduction of proin-
flammatory mediators such as prostaglandin E2 and nitric
oxide (NO; Costa et al., 2007). In a randomized, double-
blind, placebo-controlled clinical trial, patients with
chronic painful diabetic neuropathy were treated with
Sativex, an oromucosal spray containing THC and CBD,
or placebo for 10 weeks. Three types of pain (superficial,
deep, and muscular pain) were evaluated by VAS, Neuro-
pathic Pain Scale (NPS), and Total Pain Score (TPS). QOL
was assessed by MPQ and QOL, SF-36 Health Survey, and
Euro QOL questionnaires. Despite the improvement in
some outcomes compared to baseline values, no signifi-
cant difference was observed between the Sativex group
and placebo (Selvarajah et al., 2010).
Citrullus colocynthis (L.) Schrad. (colocynth) from
Cucurbitaceae family widely grows in Asia. The fruit pulp
has bitter components, including colocynthetin and colo-
cynthin, which demonstrated significant pharmacologic
effects in the treatment of diabetes mellitus (Huseini
et  al., 2009). The plant has previously exhibited analge-
sic and anti-inflammatory properties in animal models
(Marzouk et al., 2010; Ramanathan et al., 2011). In a ran-
domized, double-blind, placebo-controlled clinical trial,
the efficacy and safety of a topical product from C. colo-
cynthis were investigated in 60 patients with painful
F. Ebrahimi et al.: Herbal medicines for neuropathies      7
diabetic polyneuropathy. Sesame oil was used as a vehicle
for the preparation of colocynth oil and was individually
administered as placebo. Both groups were given 2 ml of
the topical formulation of the herbal extract or placebo
twice a day for 3 months. There was a significant improve-
ment in pain scores of both groups in comparison to the
baseline values with a significantly higher improvement
in the treatment group. Nerve conduction velocity (NCV)
of the tibial nerve, distal latency of the superficial pero-
neal nerve (SPN) and sural nerve, and sensory amplitude
of the sural nerve all were improved more significantly in
the drug group than in placebo. A significant improve-
ment of the World Health Organization QOL-Biomedical
Research and Education Foundation (WHOQOL-BREF)
was demonstrated in the drug group. There was a sign of
mild pruritus as a symptom of allergy in one case. Nine
patients complained about the greasy sensation that was
related to oily base of the formulation. Studies suggested
that the therapeutic effect of colocynth oil was due to the
antioxidant effects and/or alkaloid components with anti-
inflammatory and anesthetic effects (Heydari et al., 2016).
Goshajinkigan (GJG), a traditional Japanese polyherbal
medicine containing spray-dried extract of 10  medicinal
plants (Rehmanniae radix, Achyranthis radix, Corni fructus,
Dioscoreae rhizoma, Hoelen, Plantaginis semen, Alismatis
rhizoma, Moutan cortex, Cinnamomi Cortex, and Aconiti
radix), is used to relieve problems such as numbness, cold
sensation, and pain. It has demonstrated vasodilating
effects in streptozotocin-induced diabetic animals as well
as improvement in peripheral circulation disorders in the
diabetic state as a result of increases in NO production (Hu
et al., 2003). In a clinical trial, a total of 116 diabetic subjects
were randomly divided into two groups of GJG (74 patients)
and control (42 patients). All of the subjects received a spe-
cific diet and physical activity during the study period. The
median follow-up course for the GJG and control groups was
18 and 15 months, respectively. The HbA1c level in the GJG
group showed a higher decrease compared to the control
group. The development of ankle reflex degree was higher
in the control group; however, it was not defined if the neu-
rological improvement was through the improvement in gly-
cemic control or not (Watanabe et al., 2014).
The effect of a Chinese polyherbal formula Huangqi
Guizhi Wuwu Tang (MHGWT) on neuropathic pain in dia-
betic patients was evaluated in a randomized, double-
blind, placebo-controlled trial for 12  weeks. The mean
score of the Short-Form BPI in the daily life and sensory
domains in the MHGWT group was significantly improved
in comparison to placebo. A significant improvement in
the mean score of the Modified Michigan Neuropathy
Screening Instrument (MMNSI) was observed in both
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM
8      F. Ebrahimi et al.: Herbal medicines for neuropathies
groups after 4 to 8 and 13 weeks. Some side effects such
as dry mouth, constipation, and bitter sensation in the
mouth were reported rarely in the study, but no severe
side effects were observed with MHGWT, which suggest
the drug to be safe (Tsai et al., 2013).
In a clinical trial, 60 patients with diabetes mellitus
and distal signs of symmetrical polyneuropathy were
treated with Guduchyadi Kwatha (an ayurvedic polyherbal
formulation; (Tinospora cordifolia, Prunus cerasoides,
Pterocarpus santalinus, Azadirachta indica, and Corian-
drum sativum) for 3 months. A significant improvement in
burning pain, signs of vibration sensation, monofilament
test, pinprick, and tingling sensation was recorded. No
hypoglycemia was observed during the study. The antioxi-
dant effect of this herbal drug to protect cells from oxida-
tive damage and the improvement in physiologic activities
of patients were suggested to be the main mechanisms of
action (Parveen and Sarma, 2016).
HIV-associated neuropathy
Almost one third of patients with AIDS experience HIV-
associated distal sensory polyneuropathy (DSP). The pain
is usually symmetric with stocking-glove distribution. The
etiology of this type of neuropathy is not yet completely
understood, but it seems to result from the direct invasion
of the virus to the peripheral nerves. The production of
cytokine free radicals can also be involved in the patho-
genesis of the problem. Neuropathy in HIV patients can
also be caused by antiretroviral treatments such as dide-
oxynucleoside (Herzberg and Sagen, 2001; Schutz and
Robinson-Papp, 2013).
Capsaicin is a component that is found in Capsicum
species in Solanaceae family, such as Capsicum annuum L.
Capsaicin has selective effects on the peripheral sensory
nervous system and some pharmacological effects on pain
in diseases such as rheumatoid arthritis, postherpetic
neuralgia, and postmastectomy pain syndrome (Surh
and Li, 1996). The effect of high concentration capsaicin
patch in HIV-DSP was investigated in 274 patients with
moderate to severe pain in their feet. Pain was evaluated
by the Numeric Pain Rating Scale. Before applying patch,
patients used a topical local anesthetic (lidocaine 4%
cream) for 60 min and then capsaicin patch was applied
on the painful area of the feet. Patients were investigated
for 2 h after removing the patches. At the end of 12 weeks,
pain reduction was more significant in the capsaicin
group compared to control. There was no decrease in
sensory function with patches (Simpson et  al., 2008a).
A therapeutic effect of capsaicin patch was previously
demonstrated in an open-label pilot study, which also
confirmed the efficacy of this formulation (Simpson et al.,
2008b). Capsaicin was formerly known to act via sub-
stance P depletion; however, today’s knowledge suggests
several other mechanisms such as TRPV1 receptors to be
involved in the antinociceptive effect of this agent (Anand
and Bley, 2011).
Chemotherapy-induced peripheral
neuropathy (CIPN)
Chemotherapy is one of the main treatment modalities in
patients with different types of cancer, which is usually
administered for a long period and is associated with
many side effects, including CIPN. Several chemotherapy
agents are reported to cause neuropathy such as borte-
zomib, thalidomide, platinum derivatives, Vinca alkaloids,
and taxanes. This kind of neuropathy is associated with
cumulative doses of the drugs and is represented by pain,
sensory, and motor deficits (Addington and Freimer, 2016).
Boswellia serrata Roxb. ex Colebr. is a plant from the
Burseraceae family, which produces an oleogum resin called
frankincense or olibanum. The resin contains a mixture of
boswellic acids with an inhibitory effect on 5-­lipoxygenase
enzyme, resulting in significant antioxidant and anti-
inflammatory effects (Gupta et al., 2000). Boswellia serrata
extract and 3-acetyl-11-keto-β-boswellic acid (AKBA) have
demonstrated neuroprotective effects in oxidative damage
in PC-12 cells via the reduction of lipid peroxidation and
reactive oxygen species generation (Sadeghnia et al., 2017).
A prospective study was performed to investigate the safety
and efficacy of OPERA, a formula containing frankincense,
α-lipoic acid (an enzyme cofactor that has an important
role in dehydrogenation in mitochondria; Packer et  al.,
1994), bromlein (a proteolytic enzyme extracted from pine-
apple with anti-inflammatory and antithrombolytic effects;
Maurer, 2001), and metylsulfonyl methane (MSM) in CIPN
for 12  weeks. A significant decrease in pain with regard
to VAS and group sensory sum score (mISS) was demon-
strated at the end of the trial. With regard to the National
Cancer Institute Common Terminology Criteria for Adverse
Events (NCI-CTCAE) score of sensory and motor neuropa-
thy, the score related to sensory neuropathy was improved.
The Total Neuropathy Score Clinical Version (TNSC) was
increased by OPERA. During the treatment period, no side
effect was observed; thus, OPERA can be effective in the
treatment of this kind of neuropathy (Desideri et al., 2017).
GJG, the Japanese traditional formulation, has dem-
onstrated an antinociceptive effect in an animal model
of paclitaxel-induced neuropathy via TRPV4 receptors as
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM

well as a protective activity against mitochondrial damage
(Matsumura et al., 2014). Another animal study also sug-
gests the TRPA1 and TRPM8 channels to be involved in
the pharmacological function of GJG (Mizuno et al., 2014).
Twenty-nine patients with colorectal cancer were under
treatment with GJG to improve peripheral neuropathy
of oxaliplatin-based chemotherapy. Patients who have
taken FOLFOX6 (oxaliplatin, 5-fluorouracil, leucoverin) or
XELOX (capecitabine, oxaliplatin, bevacizumab) regimen
more than three periods were included in the study. The
occurrence of neuropathy in patients who consumed
GJG was less than the control. No specific side effect was
reported in this study. It was concluded that GJG can be
effective in the prevention of oxaliplatin-based drug chem-
otherapy; however, the small sample size was mentioned
as one of the limitations of this study (Yoshida et  al.,
2013). In another randomized, controlled trial, 29 patients
who suffered from CIPN were divided into two groups of
GJG with vitamin B12 or vitamin B12 (control group) for
6 weeks. In the third and sixth weeks, there was no signifi-
cant change between the two groups with regard to VAS
for numbness. The ratio of current perception threshold
(CPT), the indicator of peripheral neuropathy degree, was
lower in the treatment group (Sonohata et al., 2017).
The effect of nabixomols, an oromucusal spray made
from cannabinoid extract, was investigated on CIPN.
Patients who participated in this study had neuropathic
pain for 3  months after chemotherapy with paclitaxel,
vincristine, or cisplatin. There was a significant decrease
in pain with regard to the Numeric Rating Scale for Pain
Intensity (NRS-PI). The most prevalent side effects were
fatigue, dizziness, dry mouth, and nausea; however, they
caused no withdrawal and were improved by dose regula-
tion (Lynch et al., 2014).
Carpal tunnel syndrome (CTS)
CTS is one of the most common neuropathic pain result-
ing from the compression of the median nerve in the wrist.
Weakness, anesthesia, paresthesia in the carpal nerve,
and nighttime aggravation is a typical presentation of this
kind of neuropathy (Verdugo et al., 2008). High pressure
on the nerve plays a role in the pathophysiology of CTS;
however, obesity, diabetes, thyroid malfunction, preg-
nancy, genetics, and professional factors and sometimes
neuropathy resulting from chemotherapy can also cause
CTS (Verdugo et al., 2008).
Matricaria chamomilla L. (chamomile) is a well-
known medicinal plant from Asteraceae family and can
be found in any part of the world. The plant contains
F. Ebrahimi et al.: Herbal medicines for neuropathies      9
several phytochemicals such as azulenes in the essential
oil as well as flavonoids, coumarins, and sesquiterpenes
(Singh et  al., 2010). Chamomile has shown an analgesic
effect in an animal model of CIPN, which is suggested to
be due to the interaction of apigenin with benzodiazepine
receptors (Namvaran Abbas Abad et al., 2011). The plant
also showed neuroprotective activity in aluminum fluo-
ride-induced oxidative stress in rats via the improvement
of endogenous antioxidant defense mechanisms (Ran-
pariya et  al., 2011). In a randomized, placebo-controlled
trial, topical chamomile oil (chamomile flower extracted
with sesame oil) was assessed in patients with severe CTS
for 4  weeks. A significant improvement was observed in
the Symptom Severity Score (BQ SYMPT) and Functional
Status Score (BQ FUNCT) factors at the end of the study in
the chamomile group compared to baseline and placebo.
There was a little improvement in sensory NCV of the
treatment group in comparison to placebo; however, no
significant differences in motor distal latency (MDL), com-
pound latency, and median nerve sensory distal latency
(SDL) was observed (Hashempur et al., 2015).
Linum usitatissimum L. from the Linaceae family is an
ancient medicinal plant according to records since 2000
B.C. and is a traditional plant in Mediterranean countries.
The seeds (linseed) contains polyunsaturated fatty acids
(Coskuner and Karababa, 2007). Linseed oil supplement
showed neuroprotective properties in an animal model of
ischemic brain stroke via the improvement of BDNF and
glial cell-derived neurotrophic factor (GDNF; Bagheri et al.,
2017). The oil also demonstrated significant antioxidant
properties via the restoration of CAT, SOD, and glutathione
peroxidase activity in spinal cord injury (Gholaminejhad
et al., 2017). The effect of topical linseed oil was assessed
in CTS in comparison to paraffin as placebo for 4 weeks.
A wrist splint was also used in patients of both groups.
The Boston Carpal Tunnel Questionnaire (BCTQ) SYMPT
and FUNCT and some nerve conduction study outcomes
were significantly improved in linseed oil-treated patients
compared to placebo (Hashempur et al., 2014). Also, the
results of another clinical trial designed to evaluate the
efficacy of linseed oil in patients with mild to moderate
idiopathic CTS demonstrated a significant improvement
in patients treated with linseed oil compared to control
(Setayesh et al., 2016).
Other compressive neuropathies
Curcumin (diferuloylmethane) is a polyphenolic com-
pound isolated from the rhizome of Curcuma longa L. (tur-
meric) from the Zingibraceae family, which has several
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM
10      F. Ebrahimi et al.: Herbal medicines for neuropathies
preclinical evidence as an analgesic and antioxidant via
the inhibition of prostaglandin synthesis, cyclooxyge-
nase, and lipoxygenase (Chattopadhyay et  al., 2004).
Curcumin is demonstrated to improve NCV and myelin in
an animal model of cisplatin-induced neuropathic pain
(Agthong et al., 2015).
One hundred thirty-five patients with lumber disc her-
niation or lumbar canal stenosis were divided into three
groups receiving daily amounts of dexibuprofen (800 mg),
dexibuprofen (800 mg) plus lipoic acid (800 mg), or dex-
ibuprofen (800 mg) plus two Lipicur tablets (400 mg cur-
cumin + 400 mg lipoic acid). The pain was reduced at the
end of 4 and 8  weeks in all three groups; however, this
decrease was significantly higher in the Lipicur-treated
group compared to the other two groups (p < 0.05). The
only reported side effect was gastric discomfort; thus, the
study supports the use of Lipicur supplement as a comple-
mentary treatment for this type of neuropathy (Di Pierro
and Settembre, 2013).
In a group of 66 patients with multiple sclerosis who
suffered from central pain, Sativex oromucosal spray was
evaluated regarding its analgesic effects. At the end of the
5-week trial, the evaluation of 11-point NRS (NRS-11), pain
in the treatment group was significantly reduced com-
pared to placebo. Sativex was also effective to improve
sleep disturbances (Rog et al., 2005).
In a clinical trial, patients who suffered from avulsed
brachial plexus root injury were treated with Sativex. A sig-
nificant pain reduction was revealed compared to placebo.
There was a significant improvement in sleep disturbance
score as well. Adverse effects including dizziness, somno-
lence, feeling drunk, euphoric mood, headache, nausea,
and lethargy were reported by some patients; however,
their severity was mild to moderate (Berman et al., 2004).
Idiopathic peripheral neuropathy
In a clinical study, the effects of a topical herbal product
called Neuragen PN on peripheral neuropathy was inves-
tigated. The product is a homeopathic preparation that
contains geranium oil (Pelargonium graveolens), lavender
oil (Lavandula angustifolia), bergamot oil (Citrus auran-
tium), tea tree oil (Melaleuca alternifolia), and eucalyptus
oil (Eucalyptus globulus). Sixty patients (foot sole with
plantar cutaneous related to peripheral neuropathic pain)
participated in the study. At the end of the study, there
was a significant decrease in pain using VAS. Also, in a
subgroup of participants with diabetes, 94% improve-
ment was observed with Neuragen PN, whereas only 11%
of patients in the placebo group had relief from their pain.
There was no specific side effect in observed pain reduc-
tion after drug consumption by patients (Li, 2010).
Discussion and conclusion
Investigations are in process for the discovery of natural
medicines for the treatment of neuropathy. In neurologi-
cal disorders such as multiple sclerosis (Farzaei et  al.,
2017) or in other chronic pain conditions, the long-term
use of conventional analgesics such as opioids is some-
times accompanied by unpleasant adverse effects such as
constipation or drowsiness (Ferguson, 2001). In such situ-
ation, investigating a complementary adjuvant treatment
to reduce the dose of conventional analgesic would be of a
great value. Medicinal plants have demonstrated antino-
ciceptive, analgesic, and anti-inflammatory activities both
centrally and peripherally (Almeida et al., 2001; Bahmani
et  al., 2014), which is also supported by the results of
this review. Here, we have summarized current clinical
evidence on the efficacy of medicinal plants and herbal
medicines for the management of different neuropathies.
According to the obtained results, one of the impor-
tant and worthy sources from which novel ideas can be
obtained for the treatment of neuropathy is traditional
medicine of different regions. Hashempur et al. (2014) and
Setayesh et  al. (2016) both studied the effect of linseed
oil on CTS. Linseed oil is one of the remedies suggested
in Persian medicine for the topical management of neuro-
logical pain. Another suggestion of Persian medicine for
neuropathic pain is chamomile oil, as assessed in a trial
by Hashempur et al. (2015), which was significantly effec-
tive in CTS compared to placebo (Table 1). Additionally,
GJG, a multicomponent preparation in traditional Japa-
nese medicine, has been studied for diabetic neuropathy
as well as CIPN (Table 1). This shows the need for more
attention to the traditional and folk medicines as one
of the reliable sources of new ideas to introduce natural
products to manage the condition.
Several herbal products have shown beneficial effects
in neuropathies when administered locally. One of the
most important benefits of the local (transdermal) admin-
istration of these agents is to reduce the risk of herb-drug
interactions. As discussed in several studies, medicinal
plants and their isolated phytochemicals are able to affect
the pharmacokinetics of conventional drugs via several
mechanisms such as affecting the level of drug-metabo-
lizing enzymes in liver, P-glycoprotein, or influencing the
oral absorption of conventional drugs (Bahramsoltani
et  al., 2017; Soleymani et  al., 2017). Also, some natural
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM

products such as curcuminoids have poor oral bioavail-
ability due to their high lipophilicity or are highly deac-
tivated during first-pass metabolism; thus, if properly
formulated, their local administration would solve both
problems of herb-drug interaction and low oral bioavail-
ability. There are two studies on the effect of capsaicin
patch, which showed significant improvements in HIV
patients with neuropathic pain (Table 1). As HIV patients
routinely receive a long list of conventional drugs with
narrow therapeutic indices, they are susceptible to drug
interactions. Thus, in case of suggesting complemen-
tary and alternative therapies, local dosage forms have
a higher priority than the systemic ones. Conclusively,
capsaicin patch would be a suitable suggestion to control
their neuropathy; however, it is recommended to consider
the serum concentration of this compound to become sure
that the systemically absorbed capsaicin is not clinically
concerning.
Another novel formulation that can decrease the risk
of drug interactions are oromucosal sprays such as nabixi-
mols (Table 1). This formulation provides systemic admin-
istration; as the drug absorbs from sublingual blood
vessels, it overcomes first-pass metabolism by the liver
and the total administered dose would be reduced com-
pared to oral administration.
As shortly discussed in this paper, there are several
medicinal plants with preclinical studies, suggesting
them as possible candidates for the management of neu-
ropathic pain; however, the number of clinical studies
is limited. Additionally, the main mechanisms by which
the medicinal plants and their isolated compounds have
shown antinociceptive activity include the regulation of
inflammatory pathways, prevention of oxidative damage,
involvement of different types of TRPV receptors, and dif-
ferent growth factors such as BDNF and GDNF. There are
numerous numbers of medicinal plants and phytochemi-
cals that have been demonstrated to be effective in the
modulation of the above-mentioned pathways and can
be subject of future animal and clinical studies as com-
plementary approaches to treat neuropathy. Thus, a long
path still lies ahead of new systemic and/or local herbal
treatments to be assessed in clinical trials.
Some of the herbal preparations mentioned in this
review, such as linseed oil, can be clinically recom-
mended as an over-the-counter adjuvant treatment due to
their high safety and acceptable efficacy. Cannabis deriva-
tives have also high evidence, confirming their efficacy in
different types of neuropathy; however, due to systemic
administration, they are not totally safe and must be only
prescribed by physicians. In case of several other medici-
nal plants, the current evidence is poor due to small
F. Ebrahimi et al.: Herbal medicines for neuropathies      11
sample sizes, lack of comparison between the final values
of test and control groups, and short follow-up periods;
thus, future clinical studies with proper methodologies
are essential before recommending these agents as suit-
able candidates in patients with neuropathies.
Conflict of interest statement: The authors confirm that
they have no conflicts of interest.
References
Abrams, D.I., Jay, C.A., Shade, S.B., Vizoso, H., Reda, H., Press,
S., Kelly, M.E., Rowbotham, M.C., and Petersen, K.L. (2007).
Cannabis in painful HIV-associated sensory neuropathy: a ran-
domized placebo-controlled trial. Neurology 68, 515–521.
Addington, J. and Freimer, M. (2016). Chemotherapy-induced
peripheral neuropathy: an update on the current understand-
ing [version 1; referees: 2 approved]. F1000Res. 5:1466.
Agthong, S., Kaewsema, A., and Charoensub, T. (2015). Curcumin
ameliorates functional and structural abnormalities in cispl-
atin-induced neuropathy. Exp. Neurobiol. 24, 139–145.
Almeida, R.N., Navarro, D.S., and Barbosa-Filho, J.M. (2001). Plants
with central analgesic activity. Phytomedicine 8, 310–322.
Al-Saffar, A. and Al-Fatly, B. (2018). Acute motor axonal neuropathy
in association with hepatitis E. Front. Neurol. 9, 62.
Anand, P. and Bley, K. (2011). Topical capsaicin for pain manage-
ment: therapeutic potential and mechanisms of action of the
new high-concentration capsaicin 8% patch. Br. J. Anaesth.
107, 490–502.
Andersen, H. (2014). Motor neuropathy. Handb. Clin. Neurol. 126,
81–95.
Andre, C.M., Hausman, J.F., and Guerriero, G. (2016). Cannabis
sativa: the plant of the thousand and one molecules. Front.
Plant Sci. 4, 19.
Bahmani, M., Shirzad, H., Majlesi, M., Shahinfard, N., and Rafieian-
Kopaei, M. (2014). A review study on analgesic applications
of Iranian medicinal plants. Asian Pac. J. Trop. Med. 7S1,
S43–S53.
Bahramsoltani, R., Farzaei, M.H., Farahani, M.S., and Rahimi, R.
(2015). Phytochemical constituents as future antidepressants:
a comprehensive review. Rev. Neurosci. 26, 699–719.
Bahramsoltani, R., Rahimi, R., and Farzaei, M.H. (2017). Pharmacoki-
netic interactions of curcuminoids with conventional drugs: a
review. J. Ethnopharmacol. 209, 1–12.
Bagheri, A., Talei, S., Hassanzadeh, N., Mokhtari, T., Akbari, M.,
Malek, F., Jameie, S.B., Sadeghi, Y., and Hassanzadeh, G. (2017).
The neuroprotective effects of flaxseed oil supplementation on
functional motor recovery in a model of ischemic brain stroke:
upregulation of BDNF and GDNF. Acta Med. Iran 55, 785–792.
Berman, J.S., Symonds, C., and Birch, R. (2004). Efficacy of two can-
nabis based medicinal extracts for relief of central neuropathic
pain from brachial plexus avulsion: results of a randomised
controlled trial. Pain 112, 299–306.
Chattopadhyay, I., Biswas, K., Bandyopadhyay, U., and Banerjee,
R.K. (2004). Turmeric and curcumin: biological actions and
medicinal applications. Curr. Sci. 87, 44–53.
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM
12      F. Ebrahimi et al.: Herbal medicines for neuropathies
Colloca, L., Ludman, T., Bouhassira, D., Baron, R., Dickenson, A.H.,
Yarnitsky, D., Freeman, R., Truini, A., Attal, N., Finnerup, N.B.,
et al. (2017). Neuropathic pain. Nat. Rev. Dis. Primers 16,
17002.
Comelli, F., Giagnoni, G., Bettoni, I., Colleoni, M., and Costa, B.
(2008). Antihyperalgesic effect of a Cannabis sativa extract in
a rat model of neuropathic pain: mechanisms involved. Phyto-
ther. Res. 22, 1017–1024.
Comelli, F., Bettoni, I., Colleoni, M., Giagnoni, G., and Costa, B.
(2009). Beneficial effects of a Cannabis sativa extract treat-
ment on diabetes-induced neuropathy and oxidative stress.
Phytother. Res. 23, 1678–1684.
Coskuner, Y. and Karababa, E. (2007). Some physical properties of
flaxseed (Linum usitatissimum L.). J. Food Eng. 78, 1067–1073.
Costa, B., Trovato, A.E., Comelli, F., Giagnoni, G., and Colleoni, M.
(2007). The non-psychoactive cannabis constituent cannabidiol
is an orally effective therapeutic agent in rat chronic inflamma-
tory and neuropathic pain. Eur. J. Pharmacol. 556, 75–83.
Deng, Y.C., Hua, H.M., Li, J., and Lapinskas, P. (2001). Studies on the
cultivation and uses of evening primrose (Oenothera spp.) in
China. Econ. Bot. 55, 83–92.
Desideri, I., Francolini, G., Becherini, C., Terziani, F., Delli Paoli,
C., Olmetto, E., Loi, M., Perna, M., Meattini, I., Scotti, V., et al.
(2017). Use of an α lipoic, methylsulfonylmethane and bro-
melain dietary supplement (Opera®) for chemotherapy-induced
peripheral neuropathy management, a prospective study. Med.
Oncol. 34, 46.
Di Pierro, F. and Settembre, R. (2013). Safety and efficacy of an
add-on therapy with curcumin phytosome and piperine and/or
lipoic acid in subjects with a diagnosis of peripheral neuropa-
thy treated with dexibuprofen. J. Pain Res. 6, 497–503.
Farzaei, M.H., Bahramsoltani, R., and Rahimi, R. (2016). Phytochem-
icals as adjunctive with conventional anticancer therapies.
Curr. Pharm. Des. 22, 4201–4218.
Farzaei, M.H., Shahpiri, Z., Bahramsoltani, R., Moghadam Nia, M.,
Najafi, F., and Rahimi, R. (2017). Efficacy and tolerability of
phytomedicines in multiple sclerosis patients: a review. CNS
Drugs 31, 867–889.
Farzaei, M.H., Shahpiri, Z., Mehri, M.R., Bahramsoltani, R., Rezaei,
M., Raeesdana, A., and Rahimi, R. (2018). Medicinal plants in
neurodegenerative diseases: perspective of traditional Persian
medicine. Curr. Drug Metab. 19, 429–442.
Ferguson, J.M. (2001). SSRI antidepressant medications: adverse
effects and tolerability. Prim. Care Companion J. Clin. Psychia-
try 3, 22–27.
Finnerup, N.B., Attal, N., Haroutounian, S., McNicol, E., Baron, R.,
Dworkin, R.H., Gilron, I., Haanpää, M., Hansson, P., Jensen,
T.S., et al. (2015). Pharmacotherapy for neuropathic pain in
adults: a systematic review and meta-analysis. Lancet Neurol.
14, 162–173.
Freynhagen, R., Baron, R., Tölle, T., Stemmler, E., Gockel, U.,
Stevens, M., and Maier, C. (2006). Screening of neuropathic
pain components in patients with chronic back pain associated
with nerve root compression: a prospective observational pilot
study (MIPORT). Curr. Med. Res. Opin. 22, 529–537.
Gholaminejhad, M., Arabzadeh, S., Akbari, M., Mohamadi, Y., and
Hassanzadeh, G. (2017). Anti-oxidative and neuroprotective
effects of flaxseed on experimental unilateral spinal cord injury
in rat. Contemp. Med. Sci. 3, 213–217.
Grover, J.K., Yadav, S., and Vats, V. (2002). Medicinal plants of India
with anti-diabetic potential. J. Ethnopharmacol. 81, 81–100.
Grunewald, S., Matthijs, G., and Jaeken, J. (2002). Congenital disor-
ders of glycosylation: a review. Pediatr. Res. 52, 618–624.
Gupta, I., Parihar, A., Malhotra, P., Gupta, S., Lüdtke, R., Safayhi, H.,
and Ammon, H.P. (2000). Effects of gum resin of Boswellia ser-
rata in patients with chronic colitis. Planta Med. 67, 391–395.
Hashempur, M.H., Homayouni, K., Ashraf, A., Salehi, A., Taghizadeh,
M., and Heydari, M. (2014). Effect of Linum usitatissimum L.
(linseed) oil on mild and moderate carpal tunnel syndrome:
a randomized, double-blind, placebo-controlled clinical trial.
Daru 22, 43.
Hashempur, M.H., Lari, Z.N., Ghoreishi, P.S., Daneshfard, B.,
Ghasemi, M.S., Homayouni, K., and Zargaran, A. (2015). A pilot
randomized double-blind placebo-controlled trial on topical
chamomile (Matricaria chamomilla L.) oil for severe carpal tun-
nel syndrome. Complement. Ther. Clin. Pract. 21, 223–228.
Herzberg, U. and Sagen, J. (2001). Peripheral nerve exposure to HIV
viral envelope protein gp120 induces neuropathic pain and
spinal gliosis. J. Neuroimmunol. 116, 29–39.
Heydari, M., Shams, M., Hashempur, M.H., Zargaran, A., Dalfardi,
B., and Borhani-Haghighi, A. (2015). The origin of the concept
of neuropathic pain in early medieval Persia (9th–12th century
CE). Acta Med. Hist. Adriat. 2, 9–22.
Heydari, M., Homayouni, K., Hashempur, M.H., and Shams, M.
(2016). Topical Citrullus colocynthis (bitter apple) extract oil
in painful diabetic neuropathy: a double-blind randomized
placebo-controlled clinical trial. J. Diabetes 8, 246–252.
Hu, X., Sato, J., Oshida, Y., Xu, M., Bajotto, G., and Sato, Y. (2003).
Effect of Gosha-jinki-gan (Chinese herbal medicine: Niu-Che-
Sen-Qi-Wan) on insulin resistance in streptozotocin-induced
diabetic rats. Diabetes Res. Clin. Pract. 59, 103–111.
Huseini, H.F., Darvishzadeh, F., Heshmat, R., Jafariazar, Z., Raza, M.,
and Larijani, B. (2009). The clinical investigation of Citrullus
colocynthis (L.) Schrad fruit in treatment of type II diabetic
patients: a randomized, double blind, placebo-controlled clini-
cal trial. Phytother. Res. 23, 1186–1189.
Jadad, A.R., Moore, R.A., Carroll, D., Jenkinson, C., Reynolds, D.J.,
Gavaghan, D.J., and McQuay, H.J. (1996). Assessing the quality
of reports of randomized clinical trials: is blinding necessary?
Control. Clin. Trials 17, 1–12.
Jamal, G.A. and Carmichael, H. (1990). The effect of γ-linolenic acid
on human diabetic peripheral neuropathy: a double-blind
placebo-controlled trial. Diabetes Med. 7, 319–323.
Kaku, H., Kumagai, S., Onoue, H., Takada, A., Shoji, T., Miura, F.,
Yoshizaki, A., Sato, S., Kigawa, J., Arai, T., et al. (2012). Objec-
tive evaluation of the alleviating effects of Goshajinkigan
on peripheral neuropathy induced by paclitaxel/carboplatin
therapy: a multicenter collaborative study. Exp. Ther. Med. 3,
60–65.
Khanna, A.K., Rizvi, F., and Chander, R. (2002). Lipid lowering activ-
ity of Phyllanthus niruri in hyperlipemic rats. J. Ethnopharma-
col. 82, 19–22.
Lee, N.Y., Khoo, W.K., Adnan, M.A., Mahalingam, T.P., Fernandez,
A.R., and Jeevaratnam, K. (2016). The pharmacological poten-
tial of Phyllanthus niruri. J. Pharm. Pharmacol. 68, 953–969.
Li, L. (2010). The effect of Neuragen PN® on neuropathic pain: a ran-
domized, double blind, placebo controlled clinical trial. BMC
Complement. Altern. Med. 10, 22.
Lim, H.S., Kim, B.Y., Kim, Y.J., and Jeong, S.J. (2018). Phytochemical
allylguaiacol exerts a neuroprotective effect on hippocampal
cells and ameliorates scopolamine-induced memory impair-
ment in mice. Behav. Brain Res. 339, 261–268.
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM

Lynch, M.E., Cesar-Rittenberg, P., and Hohmann, A.G. (2014). A
double-blind, placebo-controlled, crossover pilot trial with
extension using an oral mucosal cannabinoid extract for
treatment of chemotherapy-induced neuropathic pain. J. Pain
Symptom Manag. 47, 166–173.
Mahady, G.B. (2001). Ginkgo biloba: a review of quality, safety and
efficacy. Nutr. Clin. Care 4, 140–147.
Marzouk, B., Marzouk, Z., Haloui, E., Fenina, N., Bouraoui, A., and
Aouni, M. (2010). Screening of analgesic and anti-inflammatory
activities of Citrullus colocynthis from southern Tunisia. J.
Ethnopharmacol. 128, 15–19.
Matlawska, I. and Sikorska, M. (2002). Flavonoid compounds in the
flowers of Abutilon indium (L.) sweet (Malvaceae). Acta Pol.
Pharm. 59, 227–229.
Matsumura, Y., Yokoyama, Y., Hirakawa, H., Shigeto, T., Futagami,
M., and Mizunuma, H. (2014). The prophylactic effects of a
traditional Japanese medicine, goshajinkigan, on paclitaxel-
induced peripheral neuropathy and its mechanism of action.
Mol. Pain 10, 61.
Maurer, H.R. (2001). Bromelain: biochemistry, pharmacology and
medical use. Cell. Mol. Life. Sci. 58, 1234–1245.
Misery, L., Brenaut, E., Le Garrec, R., Abasq, C., Genestet, S., Mar-
corelles, P., and Zagnoli, F. (2014). Neuropathic pruritus. Nat.
Rev. Neurol. 10, 408–416.
Mizuno, K., Kono, T., Suzuki, Y., Miyagi, C., Omiya, Y., Miyano, K.,
Kase, Y., and Uezono, Y. (2014). Goshajinkigan, a traditional
Japanese medicine, prevents oxaliplatin-induced acute periph-
eral neuropathy by suppressing functional alteration of TRP
channels in rat. J. Pharmacol. Sci. 125, 91–98.
Motilal, S. and Maharaj, R.G. (2013). Nutmeg extracts for painful
diabetic neuropathy: a randomized, double-blind, controlled
study. J. Altern. Complement. Med. 19, 347–352.
Namvaran Abbas Abad, A., KayateNouri, M.H., Gharjanie, A., and
Tavakoli, F. (2011). Effect of Matricaria chamomilla hydroalco-
holic extract on cisplatin-induced neuropathy in mice. Chin. J.
Nat. Med. 9, 126–131.
Numan, A., Masud, F., Khawaja, K.I., Khan, F.F., Qureshi, A.B., Burney,
S., Ashraf, K., Ahmad, N., Yousaf, M.S., Rabbani, I., et al. (2016).
Clinical and electrophysiological efficacy of leaf extract of Ginkgo
biloba L. (Ginkgoaceae) in subjects with diabetic sensorimotor
polyneuropathy. Trop. J. Pharmaceut. Res. 15, 2137–2145.
Omran, O.M. (2012). Histopathological study of evening primrose
oil effects on experimental diabetic neuropathy. Ultrastruct.
Pathol. 36, 222–227.
Packer, L., Witt, E.H., and Tritschler, H.J. (1994). α-Lipoic acid as a
biological antioxidant. Free Radical Biol. Med. 19, 227–250.
Parveen, R. and Sarma, B.P. (2016). A clinical study to evaluate the
efficacy of guduchyadi kwath in the management of diabetic
polyneuropathy. Int. J. Res. Ayurveda Pharm. 7, 17–22.
Patel, K., Patel, M., and Gupta, S.N. (2011). Effect of Atibalamula and
Bhumyamalaki on thirty-three patients of diabetic neuropathy.
Ayu 32, 353–356.
Ramanathan, T., Gurudeeban, S., and Satyavani, K. (2011). Local
anesthetic effect of Citrullus colocynthis on Rana hexadactyla.
Res. J. Med. Plant 5, 338–342.
Ranpariya, V.L., Parmar, S.K., Sheth, N.R., and Chandrashekhar, V.M.
(2011). Neuroprotective activity of Matricaria recutita against
fluoride-induced stress in rats. Pharm. Biol. 49, 696–701.
Rao, D.B., Jortner, B.S., and Sills, R.C. (2014). Animal models of
peripheral neuropathy due to environmental toxicants. ILAR J.
54, 315–323.
F. Ebrahimi et al.: Herbal medicines for neuropathies      13
Rog, D.J., Nurmikko, T.J., Friede, T., and Young, C.A. (2005). Rand-
omized, controlled trial of cannabis-based medicine in central
pain in multiple sclerosis. Neurology 65, 812–819.
Sacco, I.C.N, Suda, E.Y., and Gomes, A.A. (2017). Management
of neuropathy musculoskeletal deficits is much more than
general global exercises: physiotherapy-based programs for
diabetes long-term complications. J. Appl. Physiol. (1985) 122,
1523–1524.
Sadeghnia, H.R., Arjmand, F., and Ghorbani, A. (2017). Neuropro-
tective effect of Boswellia serrata and its active constituent
acetyl-11-keto-β-boswellic acid against oxygen-glucose-serum
deprivation-induced cell injury. Acta Pol. Pharm. 74, 911–920.
Schutz, S.G. and Robinson-Papp, J. (2013). HIV-related neuropathy:
current perspectives. HIV AIDS (Auckl.) 5, 243–253.
Selvarajah, D., Gandhi, R., Emery, C.J., and Tesfaye, S. (2010).
Randomized placebo-controlled double-blind clinical trial of
cannabis-based medicinal product (Sativex) in painful diabetic
neuropathy: depression is a major confounding factor. Diabe-
tes Care 33, 128–130.
Setayesh, M., Sadeghifar, A.R., Nakhaee, N., Kamalinejad, M.,
and Rezaeizadeh, H. (2016). A topical gel from flax seed oil
compared with hand splint in carpal tunnel syndrome: a rand-
omized clinical trial. J. Evid. Based Complement. Altern. Med.
22, 462–467.
Shahpiri, Z., Bahramsoltani, R., Farzaei, M.H., Farzaei, F, and
Rahimi, R. (2016). Phytochemicals as future drugs for Parkin-
son’s disease: a comprehensive review. Rev. Neurosci. 27,
651–668.
Sharma, S., Chopra, K., and Kulkarni, S.K. (2007). Effect of insulin
and its combination with resveratrol or curcumin in attenuation
of diabetic neuropathic pain: participation of nitric oxide and
TNF-α. Phytother. Res. 21, 278–283.
Shetty, N.S. and Shah, I. (2018). Isoniazid-induced neuropathy in
a pre-pubertal child. Paediatr. Int. Child Health, 1–3. https://
www.tandfonline.com/doi/abs/10.1080/20469047.2018.
1482996?journalCode=ypch20.
Simpson, D.M., Brown, S., Tobias, J., and NGX-4010 C107 Study
Group. (2008a). Controlled trial of high-concentration capsaicin
patch for treatment of painful HIV neuropathy. Neurology 70,
2305–2313.
Simpson, D.M., Estanislao, L., Brown, S.J., and Sampson, J. (2008b).
An open-label pilot study of high-concentration capsaicin
patch in painful HIV neuropathy. J. Pain Symptom Manag. 35,
299–306.
Singh, O., Khanam, Z., Misra, N., and Srivastava, M.K. (2010).
Chamomile (Matricaria chamomilla L.): an overview. Pharma-
cogn. Rev. 5, 82–96.
Singh, R., Kishore, L., and Kaur, N. (2014). Diabetic peripheral neu-
ropathy: current perspective and future directions. Pharmacol.
Res. 80, 21–35.
Soleymani, S., Bahramsoltani, R., Rahimi, R., and Abdollahi, M.
(2017). Clinical risks of St. John’s wort (Hypericum perfora-
tum) co-administration. Expert Opin. Drug Metab. Toxicol. 13,
1047–1062.
Sonohata, M., Tsuruta, T., Mine, H., Asami, A., Ishii, H., Tsunoda, K.,
and Mawatari, M. (2017). The effect of carpal tunnel release on
neuropathic pain in carpal tunnel syndrome. Pain Res. Manag.
2017, 8098473.
Surh, Y.J. and Li, S.S. (1996). Capsaicin in hot chili pepper: carcino-
gen, co-carcinogen or anticarcinogen? Food Chem. Toxicol. 34,
313–316.
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM
14      F. Ebrahimi et al.: Herbal medicines for neuropathies
Tajuddin, Ahmad, S., Latif, A., Qasmi, I.A., and Amin, K.M. (2005).
An experimental study of sexual function improving effect of
Myristica fragrans Houtt. (nutmeg). BMC Complement. Altern.
Med. 5, 16.
Taliyan, R. and Sharma, P.L. (2012). Protective effect and potential
mechanism of Ginkgo biloba extract EGb 761 on STZ-induced
neuropathic pain in rats. Phytother. Res. 26, 1823–1829.
Tsai, C.I., Li, T.C., Chang, M.H., Lin, S.Y., Lee, I.T., Lee, C.H., Wang,
T.Y., and Su, Y.C. (2013). Chinese medicinal formula (MHGWT)
for relieving diabetic neuropathic pain: a randomized, double-
blind, placebo-controlled trial. Evid. Based Complement.
Alternat. Med. 2013, 767498.
Verdugo, R.J., Salinas, R.A., Castillo, J.L., and Cea, J.G. (2008). Surgi-
cal versus non-surgical treatment for carpal tunnel syndrome.
Cochrane Database Syst. Rev. CD001552.
Watanabe, K., Shimada, A., Miyaki, K., Hirakata, A., Matsuoka, K.,
Omae, K., and Takei, I. (2014). Long-term effects of goshajinki-
gan in prevention of diabetic complications: A randomized
open-labeled clinical trial. Evid. Based Complement. Alternat.
Med. 2014, 128726.
Watson, C.P., Moulin, D., Watt-Watson, J., Gordon, A., and Eisenhof-
fer, J. (2003). Controlled-release oxycodone relieves neuro-
pathic pain: a randomized controlled trial in painful diabetic
neuropathy. Pain 205, 71–78.
Yoshida, N., Hosokawa, T., Ishikawa, T., Yagi, N., Kokura, S., Naito,
Y., Nakanishi, M., Kokuba, Y., Otsuji, E., Kuroboshi, H., et al.
(2013). Efficacy of goshajinkigan for oxaliplatin-induced periph-
eral neuropathy in colorectal cancer patients. J. Oncol. 2013,
139740.
Zhao, Q., Liu, C., Shen, X., Xiao, L., Wang, H., Liu, P., Wang, L.,
and Xu, H. (2017). Cytoprotective effects of myristicin against
hypoxia induced apoptosis and endoplasmic reticulum
stress in rat dorsal root ganglion neurons. Mol. Med. Rep. 15,
2280–2288.
Brought to you by | Lund University Libraries
Authenticated
Download Date | 2/16/19 12:24 PM