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      Is Open Access

      Cannabis Extract CT-921 Has a High Efficacy–Adverse Effect Profile in a Neuropathic Pain Model

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          Abstract

          Background

          Legalization of cannabis encourages the development of specific cultivars to treat disease such as neuropathic pain. Because of the large number of cultivars, it is necessary to prioritize extracts before proceeding to clinical trials.

          Purpose

          To compare extracts of two unique cannabis cultivars (CT-921, CT-928) for treatment of neuropathic pain induced by constriction of sciatic nerve in mice and to illustrate the use of this animal model to set priority for future trials.

          Methods

          Pain severity was measured by threshold force causing paw withdrawal. Dose–response relationships and time course were determined for intravenously injected extracts of cultivars and vehicle. The doses for allodynia relief were correlated with decreased respiratory rate, temperature and behavioral changes.

          Results

          Effective analgesic dose for 50 and 95% (ED 50An and ED 95An) was 15, and 29 mg/kg for CT-921 and 0.9 and 4.7 for CT-928. At ED 50An, for both extracts, the duration was 120 min. At ED 95An, administration of CT-928 significantly decreased respiratory rate while CT-921 did not. CT-928 decreased temperature more than CT-921. CT-928 produced frantic hyperactivity not seen with CT-921. At equivalent analgesic doses, THC was much less in CT-921 than in CT-928 suggesting interactions with components other than THC influenced the analgesia. At equivalent analgesic doses, efficacy-to-adverse effect profile for CT-928 was worse than for CT-921.

          Conclusion

          Both extracts relieved neuropathic pain; however, CT-921 had a better efficacy-to-adverse effect profile, a rational basis for prioritizing cultivars for future clinical evaluation.

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          Most cited references 28

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          Studying sex and gender differences in pain and analgesia: a consensus report.

          In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?"
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            Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.

            Cannabinoids are known to have analgesic properties. We evaluated the effect of oro-mucosal sativex, (THC: CBD), an endocannabinoid system modulator, on pain and allodynia, in 125 patients with neuropathic pain of peripheral origin in a five-week, randomised, double-blind, placebo-controlled, parallel design trial. Patients remained on their existing stable analgesia. A self-titrating regimen was used to optimise drug administration. Sixty-three patients were randomised to receive sativex and 62 placebo. The mean reduction in pain intensity scores (primary outcome measure) was greater in patients receiving sativex than placebo (mean adjusted scores -1.48 points vs. -0.52 points on a 0-10 Numerical Rating Scale (p=0.004; 95% CI: -1.59, -0.32). Improvements in Neuropathic Pain Scale composite score (p=0.007), sleep NRS (p=0.001), dynamic allodynia (p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) and Patient's Global Impression of Change (p<0.001) were similarly greater on sativex vs. placebo. Sedative and gastrointestinal side effects were reported more commonly by patients on active medication. Of all participants, 18% on sativex and 3% on placebo withdrew during the study. An open-label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks.
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              • Article: not found

              Sex differences in cannabinoid pharmacology: a reflection of differences in the endocannabinoid system?

              Marijuana is the most widely used illicit drug in the U.S., and marijuana use by women is on the rise. Women have been found to be more susceptible to the development of cannabinoid abuse and dependence, have more severe withdrawal symptoms, and are more likely to relapse than men. The majority of research in humans suggests that women are more likely to be affected by cannabinoids than men, with reports of enhanced and decreased performance on various tasks. In rodents, females are more sensitive than males to effects of cannabinoids on tests of antinociception, motor activity, and reinforcing efficacy. Studies on effects of cannabinoid exposure during adolescence in both humans and rodents suggest that female adolescents are more likely than male adolescents to be deleteriously affected by cannabinoids. Sex differences in response to cannabinoids appear to be due to activational and perhaps organizational effects of gonadal hormones, with estradiol identified as the hormone that contributes most to the sexually dimorphic effects of cannabinoids in adults. Many, but not all sexually dimorphic effects of exogenous cannabinoids can be attributed to a sexually dimorphic endocannabinoid system in rodents, although the same has not yet been established firmly for humans. A greater understanding of the mechanisms underlying sexually dimorphic effects of cannabinoids will facilitate development of sex-specific approaches to treat marijuana dependence and to use cannabinoid-based medications therapeutically. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                17 August 2020
                2020
                : 14
                : 3351-3361
                Affiliations
                [1 ]Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia , Vancouver, British Columbia, Canada
                Author notes
                Correspondence: Ernest Puil Tel +1 604 822 5080Fax +1 604 822 6012 Email puil@mail.ubc.ca
                Article
                247584
                10.2147/DDDT.S247584
                7443010
                © 2020 Rouhollahi et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 3, Tables: 6, References: 43, Pages: 11
                Funding
                Funded by: Cannevert Therapeutics Ltd;
                Cannevert Therapeutics Ltd sponsored this trial. They provided the cannabis extracts, animals and technical support. They were not involved in the study design or the submission of the manuscript for publication.
                Categories
                Original Research

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