Cannabis -vs- Neuropathy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481530: The age-dependent decline in brain-derived neurotrophic factor (BDNF) expression plays a crucial role in the chain of events leading to functional deficits. BDNF signalling regulates morphological and physiological synaptic plasticity , and restoration of BDNF levels was crucial for the rescue of synaptic plasticity in aged animals . Application of CB1 receptor agonists increased BDNF expression both in vitro and in vivo [207,208], which may significantly contribute to the neuroprotective effect of the cannabinoids. This hypothesis was supported by Marsicano showing that induction of BDNF expression contributes to the protective effect of CB1 receptor activity against excitotoxicity . CB1 receptor activity can enhance TrkB signalling partly by activating MAP kinase/ERK kinase pathways  but also by directly transactivating the TrkB receptors . The fact that genetic deletion of CB1 receptors leads to a decreased BDNF expression suggests that endogenous cannabinoids exert a tonic control over BDNF expression . Clinical data testing the BDNF levels in marijuana users and control individuals  also support the role of CB1 receptor activity on BDNF expression.
Besides influencing synaptic plasticity, cannabinoid system activity also facilitates embryonic and adult neurogenesis. Neural progenitor cells express the elements of the cannabinoid system, and thus actively use endocannabinoids as signalling molecules . Activation of cannabinoid receptors by agonists [215,216] or by elevation of endocannabinoid levels [215,217,218] promotes cell proliferation, neurogenesis and neuronal diversification . It was shown that CB1 receptor activity is necessary for the upregulation of neurogenesis and proliferation after excitotoxic stress . In good agreement with these findings, genetic deletion of CB1 receptors leads to defective neurogenesis . The consequence of this effect on the learning phenotype is unclear but it is unrelated to the early loss of cognitive abilities in this strain .
https://www.ncbi.nlm.nih.gov/pubmed/12505705: The analysis of gene changes associated with exposure to cannabinoids is critical due to the multiple possible signaling pathways potentially affected by cannabinoid receptor activation. A comparison of altered gene profiles under two different conditions, one in vivo (chronic exposure to delta-9-THC) and the other in vitro (neuroprotection mediated by WIN55212-2), was made to determine whether it was possible to identify common genes that were affected. Up and down-regulated sets of genes are described. Genes affected in one or the other circumstance include alterations in a 14-3-3 regulator protein of PKC, CREB, BDNF and GABA receptor subunit proteins, as well as several genes associated with known cannabinoid receptor-coupled signaling pathways. Unexpectedly, several genes that were altered in both circumstances were associated with synaptic and membrane structure, motility and neuron growth. These included, neuronal cell adhesion molecule (NCAM), hyloronidan motility receptor, and myelin proteolipid protein. While the basis for involvement of these particular genes in cannabinoid receptor activated functional processes within the cell is still not well understood, awareness that significant numbers of genes and presumably proteins are changed following either acute or long-term exposure may provide new insight into their effects.
https://www.ncbi.nlm.nih.gov/pubmed/23237736: We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain.
The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950178: It’s good to see the trial of smoked cannabis in neuropathic pain reported by Ware and colleagues1 because smoking is the most common way in which patients try this drug. The authors should be congratulated for tackling the question of whether cannabis helps in neuropathic pain, particularly given that the regulatory hurdles for their trial must have been a nightmare. The question is worth investigating because of the ongoing publicity — which patients see, hear and read — that suggests an analgesic activity of cannabis in neuropathic pain, and because of the paucity of robust evidence for such an analgesic effect. If patients are not achieving a good response with conventional treatment of their pain, then they may, reasonably, wish to try cannabis. If medical cannabis is not available where a patient lives, then obtaining it will take the patient outside of the law, often for the first time in his or her life. Good evidence would at least buttress that decision.
This trial adds to the three previous studies of smoked cannabis in neuropathic pain that I could find using PubMed and reference lists. Two of these studies were restricted to neuropathic pain in patients with HIV.2,3 Wilsey and colleagues studied patients with peripheral or central neuropathic pain, whereas Ware and colleagues1 studied people with “neuropathic pain of at least three months duration due to trauma or surgery, with allodynia or hyperalgesia.”
https://www.ncbi.nlm.nih.gov/pubmed/25843054: A randomized, double-blinded, placebo controlled crossover study was conducted in 16 patients with painful diabetic peripheral neuropathy to assess the short-term efficacy and tolerability of inhaled cannabis. In a crossover design, each participant was exposed to 4 single dosing sessions of placebo or to low (1% tetrahydrocannabinol [THC]), medium (4% THC), or high (7% THC) doses of cannabis. Baseline spontaneous pain, evoked pain, and cognitive testing were performed. Subjects were then administered aerosolized cannabis or placebo and the pain intensity and subjective "highness" score was measured at 5, 15, 30, 45, and 60 minutes and then every 30 minutes for an additional 3 hours. Cognitive testing was performed at 5 and 30 minutes and then every 30 minutes for an additional 3 hours. The primary analysis compared differences in spontaneous pain over time between doses using linear mixed effects models. There was a significant difference in spontaneous pain scores between doses (P < .001). Specific significant comparisons were placebo versus low, medium, and high doses (P = .031, .04, and <.001, respectively) and high versus low and medium doses (both P < .001). There was a significant effect of the high dose on foam brush and von Frey evoked pain (both P < .001). There was a significant negative effect (impaired performance) of the high dose on 2 of the 3 neuropsychological tests (Paced Auditory Serial Addition Test, Trail Making Test Part B.
This small, short-term, placebo-controlled trial of inhaled cannabis demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain. This adds preliminary evidence to support further research on the efficacy of the cannabinoids in neuropathic pain.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728280: Cannabinoids have been studied in various types of neuropathic pain including nerve injury, chemotherapy-induced, diabetic neuropathy, etc. CB-1 receptors have been found to be upregulated in the thalamus  and the spinal cord  after nerve injury in rat models of neuropathic pain. Another study showed CB-2 receptors were induced in a localized area of spinal cord consistent with the location of nerve injury . Systemic administration of both WIN-55,212-2 and HU-210 suppressed mechanical allodynia and thermal hyperalgesia in a rat model of trigeminal neuralgia . WIN-55,212-2 also provided antinociception in a model of sciatic nerve injury, with enhanced action if administered pre-emptively . Intrathecal JWH-133, a CB-2 agonist, also significantly improved mechanical allodynia after sciatic nerve injury . Mechanical allodynia developing in diabetic rats also responds to WIN-55212-2 administration , as does thermal hyperalgesia and tactile allodynia induced in rats by the chemotherapeutic agent paclitaxel . Mechanical allodynia induced by vincristine  and cisplatin  administration in rats is suppressed through both CB-1 and CB-2 receptor agonism. Pure CB-2 agonists also decrease chemotherapy induced neuropathic pain . Furthermore, synergistic anti-nociceptive action between Δ9-THC, CBD and other extracts from cannabis in neuropathic pain has been suggested . These studies demonstrate that cannabinoids can be potentially used as analgesics in treating neuropathic pain accompanying diverse pathologies.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566631: We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling either medium dose (3.53%), low dose (1.29%), or placebo cannabis with the primary outcome being VAS pain intensity. Psychoactive side-effects, and neuropsychological performance were also evaluated. Mixed effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the two active dose groups’ results (p>0.7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo vs. low dose, 2.9 for placebo vs. medium dose, and 25 for medium vs. low dose. As these NNT are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being, for all intents and purposes, as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well-tolerated, and neuropsychological effects were of limited duration and readily reversible within 1–2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain.