Applications of Cannabinoids in Neuropathic Pain: An Updated Review.

Although cannabinoids have great therapeutic potential in neuropathic pain, there is a need to scale up its production. The production of cannabinoids is limited to the cannabis plant, which may lead to insufficient supply of quality cannabinoids for therapeutic uses. Cannabis plant as a sole source of cannabinoids faces several challenges including climatic, disease and pest control, land/agricultural space, legal issues because of abuse of plant, low quantities of minor phytocannabinoids and chemical procedures for cannabinoid isolation. A solution to this problem could be the use of biotechnological approaches such as microbes and yeast biosynthesis. This will enhance the production of cannabinoids for therapeutic use as well as increase the accessibility of rare cannabinoids for clinical use and drug testing. Biotechnological approaches could lead to the discovery and production of novel cannabinoids, which are more effective or could be used in targeted therapy. Microbial synthesis of cannabinoids can be employed to increase the yield of cannabinoids which are produced in low quantities in the cannabis plant. The selection of the microbes for the synthesis/production of cannabinoids requires certain considerations to be taken into account, such as genetic factors, genetic engineering procedures or biological tools and the pathways for the synthesis of these compounds.

Diabetic peripheral neuropathy refers to diabetes mellitus induced neuropathic conditions, which vary from one another. 159 It is also commonly termed as distal symmetric poly neuropathy or diabetic sensorimotor neuropathy. It mainly damages the nerves present in the arms and legs. More than 80% of the people with clinical diabetic neuropathy are known to be suffering from this form of neuropathies. 160 DPN is defined as the presence of symptoms and/or signs in the peripheral nerves, predominantly affecting the lower extremities in the absence of other causes of neuropathy. 161 Clinical symptoms of DPN include tingling, burning and painful sensation, sharp pin prick sensations and muscle cramps, sensitivity to touch, loss of balance and in coordination, numbness or loss of sensitivity to thermal and mechanical stimuli and insensitivity to trauma, which leads to foot ulcerations and amputations. 162 DPN, a multifactorial disorder which arises due to hyperglycemia and/or insulin deficiency, is characterized by symptoms and/or signs in the peripheral nerves, which predominantly affects the lower extremities in the absence of other factors contributing neuropathy. 163 These interrelated defects lead to a progressive unmyelinated and myelinated peripheral nerve fiber loss or damage. The pathophysiology of DPN is associated with multiple factors which makes it challenging to identify targeted therapeutic regimen for this condition. Reports have shown that metabolic excess mediated damage to the endothelial cells of blood vessels supplying blood flow initiates the pathological events in the neurons and glial cells. 164 Conversely, metabolic excess inside the dorsal root ganglions or sciatic nerves activates many alternative metabolic pathways such as the polyol pathway, hexosamine pathway, protein kinase C pathway, AGE’s formation, etc., thereby leading to redox imbalance which initiates apoptotic pathways to kill these cells. 165 Accumulating literature extensively explains the involvement of autophagic deficiency, mitochondrial dysfunction, disabled mitochondrial biogenesis, inflammation, oxidative stress, endoplasmic stress, etc., in the progression of DPN. 165 Oxidative stress has been reported recently to play key factor in advancement of DPN. 163 , 166 , 167 Oxidative stress is promoted by hyperglycemia by both non-enzymatic and enzymatic mechanisms such as non-enzymatic protein glycation and glucose reduction to sorbitol by nicotinamide dinucleotide-linked enzyme aldose reductase (AR). 163 , 166 Sorbitol accumulation in the body results in the reduction of taurine, which is an endogenous antioxidant, 168 and osmolytes, thus leading to oxidative stress. 163 , 166 , 169

Vincristine is an antimitotic drug utilized for the treatment of numerous tumors and hematologic malignancies such as breast cancer, leukemia and non-Hodgkin’s lymphomas. Microtubules are essential for nerve axons function in vesicle mediated transport and interference of these by vincristine causes axonopathy, which manifests gradually. 145 Vincristine as a chemotherapy is essential for the treatment of pediatric malignancies including medulloblastomas and neuroblastomas. Vincristine works by binding to β-tubulin leading to the inhibition of microtubule formation, which subsequently stops cell division and interrupts cancer cell growth. 146 A dose-dependent peripheral neuropathy involving sensory, autonomic and motoric interruptions are observed in most of the patients during vincristine treatment. 147 – 150 Vincristine-induced motor neuropathy is characterized by foot drop, cramps and abnormalities in gait. 151 Loss of sensory discrimination, tingling and numbness are sensory symptoms of vincristine-induced neuropathic pain. 152 Vincristine deregulates and modifies neuronal mitochondria structurally, which leads to activation of apoptotic pathway, neuronal excitability and glial cells dysfunction. 146 Vincristine induced autonomic dysfunctions are characterized by symptoms such as constipation, urinary retention, orthostatic hypotension and paralytic ileus. 153 , 154 Although vincristine has poor blood-brain barrier penetration, 155 numerous reports show that vincristine treatment cause cranial nerve palsies and CNS toxicity. 156 – 158

Pain is classified into two main types: chronic and acute, as shown in Fig. 4 . Cannabinoids are one of the potential candidates for the therapy of neuropathic, inflammatory, and cancer associated pain. 170 – 172 These cannabinoids have been studied for different neuropathy conditions in animals such as DPN, CIPN, chronic construction traumatic injury (CCI), trigeminal neuralgia, etc. A study by Lazic et al. revealed that CBD was highly effective with minimal side effects when compared to cannabis and Δ9-THC, the efficacies of which are hindered due to side effects. 173 THC and CBD reduce CCI induced mechanical allodynia in a dose dependent manner. However, side effects are less with CBD when compared to THC. Moreover, co-administration of low doses of THC and CBD significantly reduced allodynia in a biphasic dose-dependent manner with minimal side effects in an animal model of neuropathic pain. 173 Another study by Ward et al. shows the protective action of CBD in combating paclitaxel (PAC) induced neuropathic pain partly through mediation by the 5-HT 1A receptor system. 174 The combination of CBD and PAC chemotherapy was suggested because of its minimal side effects as well as its ability to attenuate CIPN. 174 Recently, CBD was recruited in phase 2 clinical trials for studying its pain-relieving effects against DPN ( NCT04679545 ). This study intends to evaluate the impact of CBD on neuropathic pain, anxiety, and sleep quality compared to a placebo control. University of Copenhagen registered in clinicaltrials.gov to study the effects of CBD in attenuating oxaliplatin or paclitaxel induced neuropathy in a phase 2 clinical trials ( NCT04582591 ). Meta-analysis of 16 studies with 1750 participants showed that cannabis-based medicines (oral mucosal spray of TCH + CBD, nabilone and dronabinol) may increase the number of people achieving 50% or greater pain relief compared with placebo. 175 In another systematic review and meta-analysis of randomized controlled trials articulated cannabis-based medicines might be effective for chronic pain treatment, based on limited evidence, primarily for neuropathic pain (NP) patients. 176 Figure 5 summarizes possible pathways by which cannabinoids attenuates neuropathic pain and other disease conditions. Two synthetic cannabis-related drug products, Dronabinol and Nabilone containing Δ9-THC are approved by the FDA for the treatment of anorexia associated with weight loss in AIDS patients and chemotherapy-induced nausea and vomiting. Another FDA approved product is CBD, a cannabis-derived compound 177 for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in children who are 2 years and above. 178 Lennox-Gastaut syndrome, a disease characterized by multiple types of seizures is usually first diagnosed in children between 3 to 5 years and usually persists into adulthood. Various anti-epileptic drugs are used as first-line treatment and CBD is used as an adjuvant therapy. 179 CBD stands as the only FDA approved treatment for the patients with Dravet syndrome. 180 Epidiolex, a pure CBD oral solution manufactured by GW pharmaceuticals received approval from the FDA when it significantly decreased the frequency of seizures in cases of treatment-resistant epilepsy from several trials. 181 – 183 CBD has been explored for potential therapeutic use in cancers, chronic pain, neurodegenerative diseases such as Alzheimer and Parkinson disease, inflammatory and psychiatric diseases. 184 , 185 However none of these trials (as shown in Tables 1 and 2 ) have been approved by the FDA for the treatment of neurodegenerative disease, chronic pain, cancers and psychiatric diseases with CBD oil. 186 , 187

Cannabis, a drug derived from the flowers and buds of the Cannabis sativa plant is used therapeutically for various diseases for centuries. 1 , 2 Since 2700 B.C., it is used by the ancient Chinese people for various medical practices such as rheumatic pain, intestinal constipation, disorders of the female reproductive system and malaria. 2 Cannabinoids are basically C21 terpenophenolic group of compounds present in Cannabis sativa L., which include their analogs and transformation products. 3 However, cannabinoids in a broader sense refer to all cannabinoid receptor ligands and its related compounds including endogenous cannabinoid receptor ligands and synthetic cannabinoid analogs. 4 Based on the source of derivation, these are classified into three types, which include (a) endocannabinoids (eCBs), endogenous animal derivatives of polyunsaturated fatty acids (PUFAs); (b) phytocannabinoids (pCBs), obtained from plants; and (c) synthetic cannabinoids. Majority of the phytocannabinoids are present in female flowers and in most aerial parts of the cannabis plants. 5 DeltΔ9-tetrahydrocannabinol (Δ9-THC), deltΔ8-tetrahydrocannabinol (Δ8-THC), and cannabinol (CBN) are examples of psychoactive cannabinoids found in cannabis plants. Cannabichromene (CBC), cannabidiol (CBD), and cannabigerol (CBG) are common non-psychoactive pCBs present in cannabis plants. 6 Many subclasses of cannabinoids have been identified, which includes CBG, the first cannabinoid to be known; cannabigerolic acid (CBGA; carboxylic acid form of CBG), the earliest known biosynthetic cannabinoid produced in cannabis plants; CBC: five CBC type cannabinoids are known mostly with C5 and a few with C3 side chains; CBD: seven CBD-type cannabinoids have been identified containing Cl, C3, C4, or C5 side chains among which C5 is prevalent; Δ9-THC and Δ8-THC types. CBG, a non-psychoactive phytocannabinoid is present in high concentrations in Cannabis sativa. CBGA is the precursor of other essential phytocannabinoids. 7 CBN and cannabinodiol (CBND) are aromatized derivatives ( Fig. 1 ), which are formed due to air oxidation of THC and CBD, respectively. 4 THCV, a naturally occurring analog of THC is non-psychoactive, neutral CB1 antagonist and functions as an agonist/antagonist of CB2 receptors depending on its dose. However, THC is psychoactive and acts as a CB1 and CB2 receptor agonist. THCV unlike THC causes hypophagic effects under fasting and non-fasting in mice. 8 Over 150 unique terpenes and 100 different cannabinoids have been identified from various types of cannabis resins. 9 Monoterpenes such as myrcene, and sesquiterpenes such as β-caryophyllene, α-humulene, bisabolo, and β-famesene are the common terpenes found in most cannabis strains. 10 Each of the numerous active cannabinoids identified in Cannabis sativa can modulate the body’s endocannabinoid system (ECS). 11 Endocannabinoids are produced naturally in the human body, which act as lipid mediators by binding to cannabinoid receptors. ECS is made up of endogenous ligands, cannabinoid receptors and the enzymes responsible for their synthesis and degradation. 11 , 12 It plays a vital role in the regulation of numerous cognitive and physiological processes of the CNS such as pain, mood, appetite, stress, and memory. 12 – 14 ECS also regulate physiological processes in the bone, reproductive system, heart, gastrointestinal tract and many other systems. 15 – 19 Phytocannabinoids are exogenous ligands for numerous receptors of the ECS. 19 Many cannabinoids which are structurally and functionally analogous to the endocannabinoids have been synthesized. 20 – 22 CB1 and CB2 are the two main isolated endocannabinoid receptors. 20 CB1 21 , 22 and CB2 22 receptors belong to the rhodopsin (Rho) family (class A) of G-protein coupled receptors (GPCRs). CB1 receptors are mainly found on the neural tissue consisting of the enteric nervous system and central and peripheral neurons. 23 CB2 receptors are mostly present in immune tissues such as T and B cells, neutrophils, epithelial cells, macrophages as well as in the CNS. 23 , 24 Figure 2 shows the distribution of the CB1 and CB2 in the human pain system. Generally, CB1 and CB2 receptors signaling are involved in the regulation of neuromodulatory and immunomodulatory functions respectively. CBG shows low binding affinity for CB1 and CB2 receptors. 25 – 27 ECS is affected due to the ability of CBG to inhibit anandamide (AEA) uptake. 28 In vitro studies demonstrate that CBD shows weak antagonistic effects towards CB1 and CB2 receptors 29 , 30 despite the findings of several reports showing its lack of affinity for these receptors. 31 Figure 3 summarizes the various applications of cannabinoids in medicine. Several studies have shown that cannabinoids have clinical applications in various diseases which are as follows. Inflammatory bowel diseases (IBD) are chronic immune-mediated diseases which include ulcerative colitis (UC) and Crohn’s disease (CD). 32 Symptoms of IBD include periods of inflammatory flares, quiescence, and relapse, which affects the patient both psychologically and emotionally. 33 The ECS, present throughout the gastrointestinal tract has been shown to play a role in regulating food intake, emesis, gastric secretion, visceral sensation and intestinal inflammation. 34 Animal studies have shown that CB1 receptor agonists reduces gastrointestinal propulsion and transit. 35 , 36 A study by Borrelli et al. has shown the benefits of CBG in the treatment of inflammatory bowel disease using a murine colitis model by the administration of dinitrobenzene sulphonic acid (DNBS) intracolonically. CBG reduced murine colitis, the macrophage production of nitric oxide and ROS production in intestinal epithelial cells. 37 Inflammation, apoptosis and antioxidant defensive mechanisms play a pivotal role in progression of various cancers. 38 – 42 There are several ongoing research into nanodrug delivery systems (NDDSs) such as liposomes to improve the safety and efficacy of chemotherapeutic agents. 42 – 44 The use of immunotoxins for cancer treatment have also been well explored. 42 , 45 CBG has been shown to bind to specific targets, which play a role in the prevention of various cancers. It is reported to be effective in xenograft models of colon cancer by acting as a TRPM8 antagonist, increasing the production of reactive oxygen species (ROS) and activating apoptotic pathways. 46 Cannabinoids administered through inhalation route in combination with nanomaterials have shown good efficacy in lung cancer. 47 Moreover, intratumoral administration of low doses of cannabinoids can also enhance the effectiveness of chemotherapeutics. 48 – 50 Combination of cannabinoids and radiotherapy also showed good anti-cancer efficacy in glioma and pancreatic cancer. 51 Common side effects of cytotoxic chemotherapy such as muscle wasting, anorexia, and metabolic dysregulation pose dose-limiting effect on the efficacy of cannabinoids, which affects the quality of life and mortality. Cannabis sativa extracts and analogues of the major phytocannabinoid, Δ9-THC have been used to treat chemotherapy-induced appetite loss and nausea, but psychoactive side effects limit their clinical usage. In a study by Brierley et al., CBG has been shown to stimulate appetite in healthy rats without neuromotor side effects in an acute cachectic phenotype model induced by cisplatin (6 mg/kg i.p.) in male rats. 52 CBG (120 mg/kg) modestly increased food intake, mainly at 36–60 h, and strongly attenuated cisplatin-induced weight loss from 6.3% to 2.6% at 72 h, demonstrating the potential of CBG for the treatment of chemotherapy-induced cachexia. 52 An in vitro study by Zhang et al. has demonstrated that CBD inhibits the proliferation and colony formation of human gastric cancer (SGC-7901) cells, 53 during which an upregulation in the expression of p53 and ataxia telangiectasia-mutated gene (ATM) as well as a downregulation in the expression of p21 protein are observed after CBD treatment. CBD was shown to increase Bax expression and decrease Bcl-2 expression levels, which eventually results in upregulation of cleaved caspase-3 and 9, finally leading to apoptosis. 53 CBD increases intracellular reactive oxygen species levels and causes cell cycle arrest at the G0-G1 phase in gastric cancer cells. CBD has been reported to induce apoptosis through various mechanisms including caspase activation and ROS formation in human glioma (U87 and U373) cells. 54 The growth of C6 glioma cells was inhibited when co-cultured with CBD and tamoxifen. 55 Several reports have shown the ability of CBD to inhibit tumor cell proliferation and metastasis by inducing autophagy or apoptosis. 56 , 57 Non-psychoactive phytocannabinoids (pCBs) derived from Cannabis sativa could be a novel therapeutic option for treatment of cachexia due to their pleiotropic pharmacological activities such as appetite stimulation. A study in rats by Brierley et al. has shown that purified CBG is an appetite stimulant. 58 The effects of CBG-rich botanical drug substance (BDS), a potent non-psychoactive extract of Cannabis on feeding behavior was investigated and an increase in the total food intake was observed with CBG-BDS treatment group. CBG-BDS was concluded to be a novel appetite stimulant, which may be more potent than purified CBG and is devoid of psychoactive Δ9-tetrahydrocannabinol. 58 A study by Colansanti et al. has demonstrated that topical chronic administration of CBN/CBG using osmotic minipumps induced reduction of intraocular pressure (IOP) in cats. However, CBN unlike CBG caused conjunctival erythema and hyperemia. 59 Different concentrations of CBN and CBG were given as a single drop or chronically using osmotic minipumps for 9 days. A single dose of CBN showed moderate effect on intraocular pressure after a single dose and it caused a more significant reduction in ocular tension during chronic administration. Although CBG had similar effects, the response was greater than CBN. A pilot study by Tomida et al. has assessed the effects of low doses of CBD and Δ−9-THC on intraocular pressure (IOP) when administered through sublingual route. In this study, various concentrations of CBD and Δ−9-THC were given to six patients with ocular hypertension or early primary open angle glaucoma. IOP was temporarily reduced by a single 5 mg sublingual dose of Δ−9-THC. However, 20 mg CBD did not show reduction in IOP, whereas there was a transient increase in IOP when 40 mg CBD was administered sublingually. 60 Fellous et al. explored the potential therapeutic effects of Cannabis sativa plant (or phytocannabinoids) derived non-euphoric compounds including tetrahydrocannabivarin (THCV), CBD, CBG, cannabidiolic acid (CBDA) and CBGA on the growth of endogenous BM-MSCs and the alterations on cellular differentiation into mature adipocytes. 61 In vitro and in vivo experiments revealed that 5 μM of CBD, CBDA, CBGA and THCV increase the viability of BM-MSCs. CBG and CBD either alone or in combination stimulate BM-MSCs to mature into adipocytes via distinct molecular mechanisms. Phytocannabinoids further prevented the palmitate-induced insulin signaling impairment in adipocytes differentiated from BM-MSCs. Phytocannabinoids were suggested as a potential novel pharmacological tool to regain control of the functionality of adipose tissue in metabolic disorders such as type 2 diabetes mellitus (T2DM) and lipodystrophy. 61 All the classes of cannabinoids interact with the skin cannabinoid receptors and regulate the pathways, which affect the homeostasis and metabolism of skin appendages and cutaneous cells. 62 Due to the ability of phytocannabinoids to inhibit keratinocytes proliferation and modulate even the associated inflammatory components, phytocannabinoids serve as a potential treatment for psoriasis. 63 A patent was filed in 2019 on topical CBD and CBG treatment for psoriasis. CBD and CBG have been shown to be effective in trail subjects in a dose-dependent manner by inhibiting inflammatory cytokines and angiogenic growth factors. 64 A study in mice has shown that topical administration of phytocannabinoids effectively alleviate 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced erythema. 65 Several in vitro and in vivo experiments have reported that phytocannabinoids inhibit sebocytes proliferation and decrease pro-inflammatory cytokines expression and sebum production. A decrease in erythema and sebum production without side effects were confirmed in a human trial which involved topical application of phytocannabinoids for 12 weeks. 66 – 68 On the contrary, CBG and cannabigerovarin (CBGV) increased sebum production in human sebocytel (SZ95) cells. 28 , 69 CBD functions as an anti-inflammatory and neuroprotective agent in neurodegenerative disorders. A study by Rajan et al. has demonstrated that CBD reversed alterations of various genes associated with oxidative stress, mitochondrial dysfunction and pathology of amyotrophic lateral sclerosis (AML) using an in vitro model system of human gingiva-derived mesenchymal stromal cells (hGMSCs). 70 Double-blind, randomized cross-over design revealed that CBD was neither effective nor toxic at a dose of 700 mg/kg in neuroleptic-free patients diagnosed with Huntington’s disease (HD). 71 A study by Zuardi et al. has demonstrated that CBD decreased stereotypy induced by dopaminergic agonists but did not induce catalepsy, an extrapyramidal side effect of antipsychotics such as haloperidol. 72 CBD at higher doses of greater than 120 mg/kg increased prolactin levels, a side effect observed similar to clozapine treatment, indicating that CBD acts as atypical antipsychotic agent. CBD decreases hyperlocomotion and prepulse inhibition (PPI) impairment induced by amphetamine, glutamate NMDA receptor non-competitive antagonists such as ketamine and MK801 in rats and mice. 73 – 76 CBD independent of NGF has showed neurorestorative potential in MPP+ model of Parkinson’s disease. 77 CBD shows reduced affinity towards endocannabinoid receptors but higher towards Transient Receptor Potential Vanilloid receptor type 1 (TRPV1). TRPV1, a non-selective channel in its active form facilitates glutamate release and Ca 2+ permeability, which cause neuronal excitability in epilepsy. Anti-epileptic action of CBD involves desensitization of TRPV1channels and normalization of intracellular Ca 2+ levels. 78 CBD also shows high affinity towards serotonin receptors such as 5-HT 1A and 5-HT 2A , which differ in their characteristics and functions. 5HT 1 receptors activated in the hippocampus increase neurotransmission whereas 5-HT 1A receptor activation in raphe nuclei leads to serotonergic neurons inhibition. 79 Δ9-THC and CBD are used therapeutically for central nervous system (CNS) diseases such as epilepsy, anxiety, depression and schizophrenic psychosis because of their neurological actions and lipophilic nature. However, Δ9-THC and CBD differ in their penetrability and disposition in the brain. The positive effects of cannabinoids on cognitive function could be due to their protective effect on blood brain barrier (BBB), cerebrovascular structure and function. CBD will not be converted to THC by the biosynthetic enzymes or pathways present in the human body. However, CBD rapidly gets cyclized to THC in acidic pH conditions of stomach, which suggests that oral administration of CBD can cause some side effects due to its conversion to THC. This study also suggests the need to explore other routes of administration such as transdermal-based for delivery of CBD in order to reduce the formation of psychoactive cannabinoids. 80 THC causes psychomotor and cognitive impairments, increased heart rate and dry mouth. However, these effects were not observed when CBD is administered orally at high doses to healthy individuals orally. 81 , 82 In another study, oral CBD (1 mg/kg body weight) administered together with THC (0.5 mg/kg body weight) to health volunteers minimized THC-induced anxiety. This shows that of CBD blocks THC-induced anxiety. 83 Oral CBD (600 mg) pretreatment significantly reduced anxiety, cognitive impairment, and discomfort in patients with generalized social anxiety disorder. 84 A double-blind study conducted at the University of Cologne revealed that CBD administered orally at a dose of 800 mg daily for 2–4 weeks showed efficacy in 42 patients with schizophrenia or schizophreniform disorder but side effects such as extrapyramidal symptoms, increased prolactin levels, and weight gain were observed. 85 CBD enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia by increasing serum anandamide levels, which suggests that anandamide deactivation inhibition may be responsible for the antipsychotic effects of CBD in the treatment of schizophrenia. 85 The cardiovascular effects of both synthetic and endogenous cannabinoids have been well demonstrated in numerous studies. 86 – 89 The key component of cannabis, Δ9-THC causes tachycardia in humans. Phytocannabinoids induce cardiovascular effects, which vary from one species to another. Cardiovascular effects observed with Δ9-THC are different in animals when compared to humans. 90 , 91 Δ9-THC causes tachycardia in humans, and conscious monkeys, 92 whereas bradycardia in other animal models. 93 – 95 The main CYP of cardiomyocytes, CYP2J2, metabolizes AEA into cardioprotective epoxides (EET-EAs). Arnold et al. assessed the CYP2J2 metabolism kinetics with AEA, Δ9-THC, Δ8-THC, CBN, CBD, CBG, and CBC. 6 Phytocannabinoids are observed to be highly catalyzed by CYP2J2 when compared to AEA. Moreover, these phytocannabinoids strongly inhibit the metabolism of AEA by CYP2J2 of which Δ9-THC has shown the strongest inhibition. 6 A study by Hao et al. has revealed the cardioprotective potential of CBD in doxorubicin-induced cardiotoxicity model. 96 Doxorubicin (DOX), a common broad-spectrum chemotherapeutic drug is limited by its dose-dependent cardiotoxicity, which may cause irreversible cardiomyopathy or heart failure. 97 DOX induces cardiotoxicity by oxidative stress, 98 , 99 nitrosative and nitrative stress, 100 , 101 dysfunction/toxicity of the mitochondria, 97 , 102 – 104 activation of proteins associated with apoptosis and necrosis, 105 as well as metabolic and lipid signaling pathway dysregulation. 106 – 108 There was significant improvement in DOX-induced cardiac dysfunction, cell death and oxidative/nitrative stress after CBD treatment. CBD promoted biogenesis and cardiac mitochondrial function, which were impaired by DOX. 96 Oral, parental and topical administration of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, ibuprofen, and naproxen are used as a current treatment for various types of arthritis (rheumatoid arthritis, septic arthritis, juvenile idiopathic arthritis). 109 Arthritis requires continuous administration of drugs to sustain the quality of life in patient and the major problem encountered is the side effects of these drugs. Novel strategies and targets are being researched as alternate treatment options to relieve the pain caused by arthritis. 110 CBD has been successfully delivered for treatment of inflammation in different species via transdermal route. 111 – 113 Despite its hydrophobicity and poor oral bioavailability, CBD has been shown to reduce inflammation and pain without side effects. A study by Hammell et al. demonstrates the efficacy of transdermal delivery of CBD in rats in reducing inflammation and pain in a Freund’s adjuvant-induced monoarthritic knee joint model. 114 CBD gels ranging from 0.6 to 62.3 mg/day showed reduction in joint swelling, infiltration of immune cells as well as synovial membrane thickening in a dose-dependent manner. A dose dependent decrease in pro-inflammatory markers were observed in the spinal cord and dorsal root ganglia. 114 Pain possesses somatosensory, motivational, cognitive, and affective properties, 115 and is an experience that engages various parts of the brain and constitute different neurochemical mechanisms. 116 Currently, the use of scaffolds as a drug delivery matrix have been successful in various fields of tissue engineering such as bone formation, periodontal regeneration, cartilage development, for artificial corneas, in tendon repair and ligaments as well as in tumors. They are also used in joint pain inflammation, osteochondrogenesis, and wound dressings. 117 Cannabinoids including THC, CBD and synthetic cannabinoids have been reported in rodents to promote eCB action in decreasing pain, inflammation, depression, and anxiety similar to the effects of direct CB1 agonists. 118 – 123 Peripheral neuropathy (PN) involves damage to multiple parts of the peripheral nerve extending from the cell body (i.e., the dorsal root ganglion or anterior horn cell) to the cell projection itself, with its myelin outer coating and axonal projection. 124 Factors responsible for the development of PN include diabetes mellitus, shingles, exposure to toxins such as lead and chemotherapies, vitamin B12 deficiency, alcoholism, autoimmune disorders such as rheumatoid arthritis, Lyme disease, syphilis, HIV, etc. 125 It can affect motor, sensory or autonomic fibers depending on the underlying cause. 125

The route of administration of cannabinoids has considerable effects on their pharmacokinetics, bioactivity, bioavailability, and effectiveness. Cannabinoids cannot be administered intravenously due to their poor water solubility. In cancer therapy, oral administration of cannabinoids may not be the most effective route due to partial degradation by the acidic environment present in stomach. 221 A study by Deiana et al. has assessed the pharmacokinetic profiles of CBD, cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV), and CBG after an acute single-dose intraperitoneal and oral administration in mice and rats. 222 A marble burying test was used to assess the pharmacodynamic-pharmacokinetic relationship of CBD when administered at a dose of 120 mg/kg through oral and intraperitoneal route in mice. Phytocannabinoids dispersed in solutol and administered orally have easily penetrated the blood-brain barrier when compared to cremophor based phytocannabinoids. However, cremophor-based phytocannabinoids administered intraperitoneally showed higher plasma and brain concentrations. CBD and CBDV show higher brain concentrations when administered orally. However, THCV and CBG were more effective when administered through intraperitoneal route. 222 CBD administered orally has shown low bioavailability due to its first-pass metabolism in both dogs and humans. 223 , 224 The pharmacokinetics of CBD were assessed in healthy dogs in a study by Bartner et al., when administered in the form of oral microencapsulated oil beads, oral CBD-infused oil or CBD-infused transdermal cream. 225 This study demonstrates that oral CBD-infused oil showed good pharmacokinetic profile. 223 , 225 Oral or intranasal administration of CBD have shown poor bioavailability. CBD has been shown in several studies in rodents to possess antidepressant-like effects, 226 – 229 but bioavailability is a major challenge in the use of CBD in clinical trials despite its significant effects in suppressing depression. 222 , 230 The administration of medical cannabis to patients is usually via inhalation, 231 , 232 spraying, 233 or oral in the form of oil, 234 capsules, 235 and cookies. 236 Oral administration of CBD or via inhalation has poor bioavailability. Xu et al. explored the pharmacokinetics and the efficacy of CBD administration over a long period via oral and intravenous routes for treating chronic mild stress (CMS). 237

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious unwanted side effect associated with the therapeutic usage of some chemotherapeutic agents in cancer patients. 126 Substances that can damage the peripheral sensory and motor neurons and cause CIPN are categorized into six groups: (a) platinum based antineoplastic drugs (oxaliplatin and cisplatin); (b) immunomodulatory drugs such as thalidomide; (c) vinca alkaloids (vincristine and vinblastine); (d) epothilones (ixabepilone); (e) proteasome inhibitors (bortezomid); and (f) the taxanes (paclitaxel and docetaxel). 127 Therapeutic usage of these drugs induce anti-cancer effects and peripheral neuropathy through different mechanisms, which include mitochondrial dysfunction, oxidative stress, microtubule disruption, neuroinflammation, and ion channel dysregulation. 128 These drugs cause peripheral sensory symptoms such as paresthesia, dysesthesia, pain, numbness, tingling, and sensitivity to touch and temperature and motor symptoms such as weakness, gait and balance disturbances. 129 CIPN is a common clinical problem that affects about 30–40% of patients receiving neurotoxic chemotherapy and leads to a significant increase in the annual healthcare costs. 130 Patients receiving chemotherapy have common side effects of which CIPN is not an exception. CIPN is characterized by symptoms such as nerve pain in the upper and lower extremities, loss of sensory and motor nerves. A systematic review on the assessment of the incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy revealed that the prevalence rate of CIPN is 68.1% and 60.0% during the first and third month after chemotherapy. 131 There are varying severities of the side effects of anticancer therapies, and some can persist over several years. A review by Stone and DeAngelis demonstrated that more than 20 chemotherapy treatments and radiotherapies may lead to syndromes, which affect the central and peripheral nervous system (PNS) irrespective of the primary disease. 132 PNS complications have been observed with at least 21 distinct chemotherapy agents including cisplatin, carboplatin and oxaliplatin. 132 Pain relates to the interruption of sensory function due to large myelinated sensory fibers damage. In CIPN, there is a general damage of PNS which affects motor and autonomic functions. PNS damage can be caused by oxidative stress, calcium homeostasis alterations, axon degeneration and membrane remodeling which results from neuroinflammation and activation of apoptotic pathways. 133 Several studies have shown the effect of platinum-based chemotherapy in causing CIPN. A study by Kelly et al. showed that high concentrations of cisplatin (10–50 μM), oxaliplatin or carboplatin (100–500 μM) in rat sensory neurons cause increased cell death and apoptosis, 134 which is mostly due to reactive oxygen species production and 8-oxoguanine DNA damage accumulation. 134 The bodies of sensory neurons located in DRG are the known targets of Pt based compounds. 135 Pt-based compounds lead to morphological changes, usually observed in the nucleoli, whose form is affected by decreased production of ribosomal RNA. The formation of DNA-Pt adducts hinders transcription thereby leading to apoptosis especially in large neuronal cells, which are generally dependent on active transcription and translation. 136 A review by Zajaczkowska et al. reveals that altered excitability of peripheral neurons is caused by Pt induced ion channels deregulation and compromised mitochondrial DNA transcription. 137 Activation of microglia and astrocytes during the initial stages of neuroinflammation was observed and this study corroborates with similar observations by Colvin et al., which shows the role of cytokines in neuronal toxicity. Generally, the mechanisms which are involved for anticancer effect of various chemotherapeutics are also responsible for the neurotoxic effect they cause. 137 The combined effect of procarbazine, CCNU and vincristine (PCV) is utilized as an adjuvant therapy in cerebral glioma recurrence. A study by Postma et al. has showed that out of 26 patients with recurrent gliomas treated with PCV, four of them developed central neurotoxic side effects including focal neurological deficit, cognitive disturbances, slow EEG background activity as well as hematological and hepatic toxicity. 138 After months of chemotherapy discontinuation, prolonged myelosuppression and neurological deficits are observed in three of these four patients. The central neurotoxic effects were hypothesized to be resulting from the intensive PCV although all four patients have previously been treated with radiotherapy and anticonvulsants. 138 Breast cancer patients treated with paclitaxel who developed neuropathy showed differential expression in several pathways involved in mitochondrial dysfunction such as oxidative stress 139 in a study by Kober et al. 140 Bioenergetic deficits in peripheral nerves have also been observed in CIPN. 141 A study by Flatters and Benner revealed that rats treated with paclitaxel had swollen vacuolated mitochondria that is usual of about 3 months of pain-like behaviors. 142 Several animal studies have shown that chemotherapy increases oxidative stress. 143 , 144