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Evidence for the analgesic effects of medicinal cannabis is still inconclusive, which is related to the high failure rate of trials of new treatments for neuropathic pain. As there are many diverse mechanisms involved in neuropathic pain and within a single etiologically homogeneous group of patients, phenotyping of well-defined subgroups of patients with uniform symptomatology is essential. Furthermore, there is evidence that cannabidiol (CBD), one of the main constituents of cannabis, acts as a negative allosteric modulator of the CB1 receptor and can therefore modulate the psychotropic effects of delta 9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis. It remains unclear what the ideal ratio between THC and CBD would be to benefit from the CB1 modulating effects of CBD, while retaining the positive effects of THC on pain. We aim to provide proof-of-principle for the hypothesis that CBD attenuates the psychotropic effects of THC, when administered at an optimal combination of THC:CBD concentrations, and proof-of-concept that cannabinoids can be analgesic when used to treat certain phenotypic subgroups of patients with chronic neuropathic pain. We will evaluate whether CBD attenuates THC side effects without affecting analgesic effects in a randomized, double-blind, 5-way cross-over study in healthy males and females. The results of this study will determine which ratio of THC:CBD will be used in a subsequent randomized, double-blind, 2-way cross-over study in patients with neuropathic pain, wherein we aim to identify in which phenotypical subgroup of patients cannabinoids have the largest treatment effect. The results of this project will add to the body of evidence regarding the effectiveness of cannabis-based medication in the treatment of chronic neuropathic pain and could provide a recommended optimal THC:CBD ratio that will most likely be effective in a certain phenotypical subgroup of patients with neuropathic pain.



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