This study examined efficacy of transdermal CBD for reduction in topical CBD application has therapeutic potential for relief of arthritis USA) was added followed by isopropyl myristate (Fisher Scientific, Fairlawn, NJ, USA). (1)Department of Pharmaceutical Sciences, University of Kentucky College of BACKGROUND: Current arthritis treatments often have side-effects attributable to METHODS: This study examined efficacy of transdermal CBD for that topical CBD application has therapeutic potential for relief of arthritis. The assessment of the therapeutic potential of MM allowed in the . in need of relief of symptoms such as chronic pain, arthritis, movement . on CBD4 to recommend MM as a potential treatment option for patients with epilepsy. . RCT set out to examine the therapeutic effects of smoked cannabis, and.
Topical CBD Of Examines ‘Therapeutic Science For Arthritis’: Potential Relief
However, there is residual uncertainty about whether the effects of cannabinoids are real. In addition, new clinical trials should explore other objective modalities such as the stretch reflex test which has demonstrated a statistically significant reduction in stretch reflex amplitude as well as statistically significant reductions in numeric rating scale NRS and MAS scores in assessing the improvement of MS-related spacticity.
Although there are indications that MM is effective in reducing patient-reported symptoms such as spasticity and pain, studies also show that cannabinoids have no proven overall effect on the progression of MS. As with MS patients who do not see an improvement in QOL following treatment, approximately one third of epileptic patients fail to respond to currently available antiepileptic drugs fully. Patients with treatment-resistant epilepsy have a higher prevalence of comorbidities, 82 , 83 psychosocial and cognitive problems, 84 negative public attitudes, 82 , 83 decreased QOL and increased risk of mortality.
We identified five new trials published since investigating the therapeutic potential of CBD in the treatment of drug-resistant epilepsy in children or young adults failing to respond to conventional anticonvulsive medications.
Partial and atonic seizures had the most significant reduction in frequency followed by tonic and tonic—clonic seizures. CBD has shown some promise as a potential medical alternative in the treatment of drug-resistant epilepsy with minimal side effects. Based on the high-quality multicentered randomized controlled trials RCTs enrolling hundreds of patients to date, 90 , 92 , 93 there is evidence that CBD is effective on Lennox Gastaut, Dravet syndrome, and other types of childhood treatment-resistant epilepsy.
In one study, a wide range of CBD is administered from 0. Given the location of cannabis receptors in the CNS, the scientific rationale for the use of MM to alleviate the symptoms associated with movement disorders is perhaps not surprising. In a double-blind clinical trial, PD patients without dementia or comorbid psychiatric conditions were assigned to one of three groups: They also demonstrated significant improvement in their sleep and pain scores just 30 minutes after smoking cannabis.
More extensive, controlled, randomized, and blinded clinical trials are required to better assess the role of cannabinoids in the treatment of PD and levodopa-associated dyskinesia, as small sample size and variability in study design limit our ability to draw definitive conclusions. Additional research is required to determine whether subsets of individuals with various neurological and psychiatric diseases derive the same therapeutic benefits from cannabis.
TS is a common neurobehavioral disorder characterized by multiple motor and phonic tics, generally starting in childhood. According to Health Canada, 18 anecdotal and case reports have suggested an improvement in symptoms associated with TS when smoking cannabis. In the first study, the patient received Both the studies demonstrated a significant reduction in motor and vocal tic severity and frequency following MM treatment.
Moreover, the second case report showed a substantial improvement in the QOL associated with MM treatment. More extensive clinical trials studying the effects of MM on alleviating TS symptoms are required for physicians to comfortably decide whether the use of MM would be an appropriate alternative option. The endocannabinoid system is vastly integrated within the GI tract, particularly within the enteric nervous system. A significant portion of self-medicating IBD patients found cannabinoids helpful for symptoms such as abdominal pain, — poor appetite, , nausea, , diarrhea, — and joint pain.
Furthermore, anecdotal data focused on the positive effects of cannabis use in the treatment of IBD, making it challenging to conclude the therapeutic efficacy of such compounds as treatment options. A concerning finding was the correlation between long-term cannabis use and increased rate of surgical procedures in IBD patients, with cannabis use potentially masking disease activity leading to worsened disease outcomes.
Future studies should focus on more substantial double-blinded RCTs to assess the efficiency and safety of MM treatment in IBD patients, focusing on optimal routes of administration and dosing. Specifically, patients with HIV who were administered non-dronabinol were reported to have a statistically significant increase in caloric intake compared to placebo, particularly in patients with substantial cachexia.
Theoretically, dronabinol studies may be applied to other forms of THC; however, the dosing, side effects, long- and short-term safety, and comparative efficacy against placebo or other appetite stimulants may differ among different formulations. Since the Health Canada document, there have been only two ongoing trials using cannabinoids in anorexia, both in the context of cancer.
However, despite the potential of MM as a therapeutic option, the fact remains that there is little-to-no clinical trial evidence guiding the use of non-dronabinol cannabinoids in anorexia. With these tenets in mind, evidence can guide the use of cannabinoids in anorexia and potentially improve patient outcomes.
According to the Health Canada document, nabilone, dronabinol, and levonantradol perform significantly better than placebo and slightly better than conventional dopamine D2-receptor antagonist anti-emetics in suppressing chemotherapy-induced nausea and vomiting CINV.
Although cannabinoids were associated with higher incidence of adverse events such as dizziness, dysphoria, euphoria, and sedation, some participants expressed a preference for cannabinoids over other antiemetics. There is still limited information on the relative efficacy of cannabinoids over the newer antiemetics such as 5-HT3 ondansetron and granisetron or neurokinin-1 receptor antagonists.
Two placebo-controlled trials on the effect of cannabinoids on postoperative nausea and vomiting were identified. Participants have been pretreated with 0.
The endocannabinoid system is a critical endogenous pain control system 27 , , as such, the targeting of this system with cannabis may provide a therapeutic advantage in the treatment of pain. The modulation of pain is thought to be due to inhibition of presynaptic neurotransmitter release and modulation of postsynaptic excitability. The Health Canada document presented mixed results in the efficacy of cannabinoids in acute, experimentally induced pain. Neuropathic pain is a complex, chronic pain state that affects over 2 million Canadians, , with half of the sufferers failing to achieve adequate relief.
Since the publication of the document, 10 relevant studies were published about cannabinoids in neuropathic pain see Table S3 for a detailed summary of trial data.
Nonetheless, these gaps should not prevent health care professionals from using marijuana and its analogs to combat neuropathic pain. Health Canada initially grouped chronic non-cancer pain with neuropathic pain; however, we believe that chronic non-cancer pain best fits into its category. Four trials found that causes of pain included functional chest pain, chronic pancreatitis-related pain, chronic abdominal pain, and unspecified chronic non-cancer pain. This contradiction of the findings creates a need for each case to be examined individually to determine the effectiveness and is the main reason for the separation of the data from the neuropathic pain section.
The results of each trial have been summarized and included in Table S3. In Canada, it is estimated that in there will be over , newly diagnosed cancer patients. Since , three studies have been published regarding cannabis use in cancer pain. The study results, excluding the observational questionnaire, are in contrast to the trials analyzed in the Health Canada document and may be attributed to small sample sizes and significant dropout rates.
Given the quality of the evidence reviewed, it can be concluded that these studies have not significantly added to the current knowledge on treatment of pain in cancer, and thus more research will be needed to clarify this. Future blinded RCT studies on the role of cannabis in the treatment of cancer pain should include examining a variety of modes of administration in large patient populations and examining both short-term and long-term efficacy and safety profiles of cannabis products. Since the Health Canada review, many survey studies, — and a chart review have studied the therapeutic efficacy of MM in the treatment of headaches, however only one controlled clinical trial was conducted.
Primary outcome measures included headache frequency, daily analgesic intake, pain intensity and duration, level of dependence, and pain-free days. While both the drugs resulted in statistically significant improvement in all primary outcomes, nabilone was superior to ibuprofen greater effect size in all parameters.
In addition, subgroup analyses showed that patients who received ibuprofen in the second half of the study crossing over from nabilone did not demonstrate ibuprofen-associated improvements seen in the overall data. Furthermore, these patients did not experience continued improvement 2 weeks following the study endpoint, unlike patients who received nabilone following treatment with ibuprofen. However, given the subjective nature of pain, the psychoactive effects of cannabinoids may be considered a new part of the therapeutic profile of cannabis if they affect the perception of pain.
Although there are some promising therapeutic applications of MM in the treatment of several conditions outlined above, a thorough understanding of patient history and specific patient subpopulations presenting with other states should be considered.
These contradictions are outlined in detail below. According to the Health Canada report, 4 there was a dose—response relationship between cannabis use and the risk of psychotic disorders. Early exposure and greater use were linked to initial symptom onset, particularly in those predisposed to mental illness.
Furthermore, cannabis use after the first psychotic episode or schizophrenia diagnosis was associated with weak prognostic features, such as multiple relapses and worse symptoms.
Since the Health Canada report, literature has confirmed a dose-dependent relationship between cannabis use and the risk of psychotic disorders. Specifically, patients with a history of cannabis use experienced their first psychotic episode from 2. Eight recent correlational studies not included in Health Canada Report investigated the effects of marijuana on schizophrenia severity, including positive and negative symptoms and level of function. However, it is noteworthy to mention that these studies are meant to provide information on patients with psychosis who use recreational cannabis and are not treatment studies.
Lastly, there was no significant difference between cannabis users and nonusers in the ability to adapt to various problems-in-living, based on the Global Assessment of Functioning GAF scale. During a follow-up period, a change in cannabis use, whether escalation or de-escalation, exhibited a reverse relationship with GAF.
As an alternative, there could have been confounding variables that were not accountable. Overall, these findings imply that not all people are affected equally by cannabis and that physicians should advocate against heavy and early cannabis use. The majority of studies did not control for treatment adherence, which is an important confounding variable, as current cannabis users are less likely to adhere to psychiatric medical therapy than nonusers and former users by a factor of 4.
CBD , cannabis being particularly noxious, is a statistically better predictor of nonadherence than low potency or infrequent use. People with psychotic illness develop a more significant decline in their cognitive abilities relative to other mood disorders. Only one study detected a diminished cognitive performance in social cognition with a long-term cannabis use.
After controlling for confounders, such as age, the age of illness onset, socioeconomic status, premorbid IQ, the effect of cannabis on cognitive function was not significant based on The Digit Symbol Coding Test.
It is possible that the disease itself exerts a stronger effect on cognitive performance than cannabis. Alternatively, a subpopulation of patients who uses marijuana could be functioning better relative to nonusers. This could explain that abstinence from cannabis resulted in statistically significant improvement in memory and learning. Physicians should strongly advise against daily or high potency cannabis use, early onset of use, and any use if it is associated with subthreshold psychotic features to prevent future psychiatric complications.
However, evidence around cannabis use during mental illness is conflicting. Currently, there is no evidence of active adverse effects for cannabis use, except for moderate exacerbation of positive symptoms, reversible effects on global function, and some cognitive domains.
Additional longitudinal research is needed to examine various levels of cannabis use on psychiatric symptoms and cognitive function with better control for confounding variables. PTSD can have a variety of triggers that affect multiple populations that are encountered within primary care, such as veterans and sexual assault victims. A recent open-label pilot study administering 5 mg THC in oil daily for 3 weeks showed a reduction in nightmare frequency. For these studies, the cognitive effects acute or chronic associated with cannabinoid use should be examined carefully in patients with cognitively demanding occupations such as active military duty, as PTSD is highly prevalent in this population.
Currently, there are multiple ongoing trials, including two in Canada, , which investigate smoked, vaporized, and ingested cannabis for use in PTSD which would help address the gaps in current knowledge and solidify the evidence for or against the use of marijuana in PTSD.
Cannabinoid receptors have been detected in the placenta, and some cannabinoids, such as THC, can cross the placenta, , accumulating in breast milk. According to the Health Canada report, the short-term effects of cannabis on neonatal outcomes were inconsistent, with some studies reporting reduced birth weight and length, — as well as a non-statistically significant trends toward sudden death, while others reported no effect.
Smoking marijuana during pregnancy had no direct effect on maternal health, labor complications, or postnatal problems; however, increased maternal anemia was reported. Cannabis users are more likely to be single, , have a low income, or be unemployed, which may predispose infants toward nutritional deficiency. It is possible that cannabis use during pregnancy has an equivalent effect on maternal health as on any other adult user. However, according to various reports, marijuana use during pregnancy falls between 3.
Furthermore, maternal cannabis consumption was associated with a However, the study is not sufficient to detect individual risks as it comprises only 48 marijuana users compared to nonusers. We could not identify any recent research on the effect of cannabis use on breastfeeding or long-term outcomes since the Health Canada report.
Such research is challenging due to the extended follow-up period needed and the presence of many confounding variables, such as parental cannabis use, socioeconomic status, family dynamic, and neighborhood influence. Although studies have reported no or transient effects of early cannabinoids exposure on growth, motor, — and cognitive development, — these earlier findings have limited applications today, given that new cannabis strains are more potent than before.
Since cannabis use during pregnancy has a noticeable effect on early childhood morbidity, physicians should strongly advise against its recreational use during pregnancy.
Pregnant women refusing or incapable of stopping cannabis use should be encouraged to obtain cannabis from approved sources where the exact amount of marijuana used can be monitored. Such information could be used in future research to quantify better cannabinoids consumed and identify dose-dependent outcomes. The new study should also consider various routes of cannabis administration, whether edible, smoked, or vaporized, and control confounding variables such as maternal health and socioeconomic status.
The widespread abuse of opioids has led to a spike in opioid-related death to 8. Methadone, buprenorphine, and naltrexone are the only three US Food and Drug Administration-approved drugs for long-term treatment of opiate addiction.
CBD may play a role due to its anti-anxiety effect, curbing the extreme anxiety associated with opioid withdrawal. Second, it has been shown that cannabinoids can cause increased glucose intake and lipogenesis.
Tolerance to THC is theorized to be due to downregulation and desensitization of CB1 , and has been documented in heavy and therapeutic users, but not in social users. A few studies examined agonist therapy with synthetic cannabinoids to attenuate withdrawal symptoms and promote cannabis use cessation. However, because opioids and cannabinoids have been shown to interact synergistically with each other, if a patient is prescribed both opioid and cannabis, care providers should know that opioid may need to be reduced to avoid dependency.
Other studies investigated vilazadone, escitalopram, buspirone, lithium carbonate, and a combination of lofexidine and dronabinol, to treat cannabis dependence, but none showed any significant results. The risk of addiction must be weighed against the benefit on a case-by-case basis. Currently, an accepted pharmacological treatment for cannabis-use disorders does not exist. In summary, the effect of cannabis has been intensely studied in several disease states, as previously discussed; however, gaps in our knowledge remain.
Bearing this in mind, our current knowledge on cannabis use suggests that cannabis presents as an appropriate alternative therapy option for patients who have epilepsy, movement disorders, and pain.
For individuals with MS, GI disorders, anorexia, and headaches, further research is recommended to improve our understanding of the effects of MM, and caution is advised when considering the authorization of MM use. For patients who are under the age of 25 years, pregnant, or present with a history of mental health and substance use, it is safe to err on the side of caution and avoid MM authorization.
Overall, MM is an exciting field of exploration, and the diverse range of receptor expression in the human body offers many therapeutic benefits, yet additional research is required for a more robust understanding and characterization of the mechanism of action of MM to achieve maximal therapeutic efficacy. The data sets supporting the conclusions of this article are included within the article and in the supplementary material.
The authors are grateful to the initial internal peer-reviewers with expertise in medicinal marijuana for their comments and suggestions for the improvement of this review article. The views expressed in this article are those of the authors and not the funding bodies.
All Authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work. M Sambi is a recipient of the QGA. The authors report no other conflicts of interest in this work. National Center for Biotechnology Information , U.
Drug Healthc Patient Saf. Published online Jun Author information Copyright and License information Disclaimer. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https: 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.
Abstract With the proposed Canadian July legalization of marijuana through the Cannabis Act, a thorough critical analysis of the current trials on the efficacy of medicinal marijuana MM as a treatment option is necessary. Introduction In Canada, marijuana or cannabis used interchangeably hereafter has been used recreationally and medicinally for generations but was first legally available as medicinal marijuana MM in through the Medical Marijuana Access Regulations.
Methods This literature search identified articles using PubMed, EMBASE Ovid, and the Cochrane Library to determine high-quality, multicenter randomized controlled trials, systematic reviews, meta-analyses, and practice guidelines from February to August Brief overview of the mechanisms of action of MM Given the pending legalization of MM for recreational purposes through the enactment of the Cannabis Act, it is important for family physicians to understand the underlying effects of cannabis.
The endocannabinoid system and MM The endocannabinoid system is a naturally occurring communication network that plays a role in many physiological processes.
Open in a separate window. Table 1 Specific effects of THC in the peripheral system. Pharmacokinetics of MM In addition to understanding the effects of phytocannabinoids on the endocannabinoid system, physicians should be mindful of the chemical composition and available routes of administration if considering the authorization of MM. Oral Oral cannabinoid administration offers a longer duration and a slower onset of action compared to inhalation, making titration challenging for patients attempting to achieve desired effects.
Oromucosal Oromucosal cannabinoid administration offers a balance between speed of onset and duration of action when compared to inhalation and oral routes.
Rectal The rectal route of cannabinoid administration, though uncommon, has been shown to be efficacious in patients presenting with chemotherapy-related nausea and emesis. Topical Topical cannabinoid administration has been considered as a treatment for glaucoma. Metabolism, excretion, and long-term detection of THC The metabolism and excretion of cannabinoids are highly regulated and affect many other metabolic processes that need to be considered if advising the medicinal use of cannabis.
Therapeutic options applicable for the authorization of MM use As previously discussed, many physicians feel uncomfortable with authorizing MM use due to a lack of educational resources available. Epilepsy As with MS patients who do not see an improvement in QOL following treatment, approximately one third of epileptic patients fail to respond to currently available antiepileptic drugs fully.
Movement disorders Given the location of cannabis receptors in the CNS, the scientific rationale for the use of MM to alleviate the symptoms associated with movement disorders is perhaps not surprising. GI disorders The endocannabinoid system is vastly integrated within the GI tract, particularly within the enteric nervous system. Nausea and vomiting According to the Health Canada document, nabilone, dronabinol, and levonantradol perform significantly better than placebo and slightly better than conventional dopamine D2-receptor antagonist anti-emetics in suppressing chemotherapy-induced nausea and vomiting CINV.
Pain The endocannabinoid system is a critical endogenous pain control system 27 , , as such, the targeting of this system with cannabis may provide a therapeutic advantage in the treatment of pain. Chronic neuropathic pain Neuropathic pain is a complex, chronic pain state that affects over 2 million Canadians, , with half of the sufferers failing to achieve adequate relief.
Chronic non-cancer-related pain Health Canada initially grouped chronic non-cancer pain with neuropathic pain; however, we believe that chronic non-cancer pain best fits into its category. Cancer-related pain In Canada, it is estimated that in there will be over , newly diagnosed cancer patients. Headaches Since the Health Canada review, many survey studies, — and a chart review have studied the therapeutic efficacy of MM in the treatment of headaches, however only one controlled clinical trial was conducted.
Special considerations Although there are some promising therapeutic applications of MM in the treatment of several conditions outlined above, a thorough understanding of patient history and specific patient subpopulations presenting with other states should be considered.
Mental health According to the Health Canada report, 4 there was a dose—response relationship between cannabis use and the risk of psychotic disorders.
Treatment adherence The majority of studies did not control for treatment adherence, which is an important confounding variable, as current cannabis users are less likely to adhere to psychiatric medical therapy than nonusers and former users by a factor of 4.
Cognition People with psychotic illness develop a more significant decline in their cognitive abilities relative to other mood disorders. Post-Traumatic Stress Disorder PTSD can have a variety of triggers that affect multiple populations that are encountered within primary care, such as veterans and sexual assault victims.
Cannabis and pregnancy Cannabinoid receptors have been detected in the placenta, and some cannabinoids, such as THC, can cross the placenta, , accumulating in breast milk. Cannabis and opioids The widespread abuse of opioids has led to a spike in opioid-related death to 8. Cannabis abuse Tolerance to THC is theorized to be due to downregulation and desensitization of CB1 , and has been documented in heavy and therapeutic users, but not in social users. Conclusion In summary, the effect of cannabis has been intensely studied in several disease states, as previously discussed; however, gaps in our knowledge remain.
Data sharing statement The data sets supporting the conclusions of this article are included within the article and in the supplementary material.
Acknowledgments The authors are grateful to the initial internal peer-reviewers with expertise in medicinal marijuana for their comments and suggestions for the improvement of this review article. Barriers to access for Canadians who use cannabis for therapeutic purposes.
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Effects of cannabis on cognitive function in patients with multiple sclerosis. Pain scores of animals that received 0. All naive rats scored 0 in this test. Baseline paw withdrawal latencies were similar in all experimental animals 10—12 s.
Hypersensitivity to noxious heat was detected in all animals with adjuvant-induced monoarthritis. Average paw withdrawal latency PWL in response to radiant heat applied to the plantar surface of the same side hindpaw, was significantly decreased on day 3 from After 2 days of treatment with 6.
Reduction in monoarthritis-induced heat hypersensitivity was maximal after 2 days of transdermal application of 6. Adjuvant-induced heat hypersensitivity was not changed by transdermal application of vehicle, nor by 0.
Daily application of CBD gel on naive animals did not alter heat sensitivity irrespective of the concentration used Fig. Transdermal cannabidiol CBD reduced monoarthritis-induced hind paw heat hypersensitivity. C, D In the open-field test, transdermal CBD exerts no detectable effect on times spent in spontaneous exploratory activity or resting.
Potential for adverse side-effects on activity levels or motor abilities stemming from CBD gel application were assessed by monitoring open-field exploratory behaviour of naive animals for 45 min prior to and directly after treatment.
Irrespective of the amount of CBD applied onto the back of animals, no changes were detected for total time spent in either exploratory activity or resting Fig.
Two other specific exploratory activities acquired in the open-field test but not affected by CBD were rearing events in which the animals rise on their hindlimbs to explore the environment and the total distance travelled during the 45 min test data not shown. After batch staining immunohistochemical methods, the intensity of immunofluorescence was determined using computer assisted quantification. The immunoreactivity for neuropeptide CGRP was significantly increased in the superficial dorsal horn of the spinal cord in the monoarthritis group.
Treatment with high doses of CBD 6. Immunocytochemical localization of inflammatory biomarkers. Quantification of pro-inflammatory biomarkers in the lumbar spinal cord and dorsal root ganglia DRG. Naive animals had low levels of OX42 expression in the spinal cord, a marker for activated microglia Fig. Outcomes of this study indicate that topical application of CBD gel is an effective treatment for reduction in inflammation and hypersensitivity associated with the rodent adjuvant-induced monoarthritis model.
Transdermal administration of CBD provided good blood absorption due to avoidance of first pass metabolism encountered by orally administered drugs. Similarly in this study, CBD plasma concentrations for rats dosed with 0. However, the highest dose, The lack of increased outcome for this highest CBD concentration was potentially due to maximally activated CBD effects or capacity-limit absorption and metabolism.
This would account for the flattened linear pharmacokinetic profile effect of the Spreading large quantities of gel directly on the skin over the joint itself was not feasible in this transdermal dosing paradigm and would provide opportunity for oral ingestion by the rats. Efficacy of transdermal CBD for reduction in inflammation-associated symptoms in adjuvant-induced monoarthritic animals was determined comparing knee joint circumference and other features.
Likewise, increased synovial membrane thickness was reduced by the 6. These results concur with previous studies showing orally administered CBD decreased inflammation Malfait et al. Decreased inflammation and reduction in secretions of pro-inflammatory and matrix-degrading effector molecules by the synovial cell connective tissue membrane lining the joints are important for symptomatic treatment of patients with rheumatoid arthritis.
Pro-inflammatory and matrix-degrading effector molecules produced in excess are primary contributors to cartilage degradation over time Ospelt et al. The improvement of pain scores provided by transdermal CBD is an indirect measure of joint inflammation and direct measure of function.
The PWL in response to noxious heat stimuli was optimal with both the 6. Analogous to the results presented here, the highest dose of CBD administered in that study also did not perform as well as the next lower dose.
In the same study at 6 h post inflammation, CBD treatment with two orally administered lower doses, 5 and 7. Peripheral inflammation and hypersensitivity are reversed by pharmacological inactivation of both central and peripheral neurons and central microglia Sluka et al.
Although CBD is described as an attenuator of both mechanical and heat hypersensitivity induced by inflammatory and neuropathic pain models, the exact mechanism of action is as yet unknown Mechoulam and Hanus, ; Kress and Kuner, Unlike THC and related cannabinoids, phytocannabinoid-CBD, an important bioactive component of Cannabis sativa without psychotropic effect, is an antagonist of orphan G protein-coupled receptor 55 GPR55, a potential third metabotropic cannabinoid receptor without binding to CB1 and CB2 receptors Begg et al.
A particular focus has been on TRPA1 and TRPV1, two widely co-expressed ion channels found in CGRP expressing peptidergic nociceptors essential for neurogenic inflammation, oedema formation and inflammation-induced mechanical and thermal hypersensitivity Davis et al. Their activation by CBD in vitro results in desensitized responses following noxious stimulation with capsaicin or mustard oil, their respective agonists.
This mechanism potentially decreases neuropeptide expression Bisogno et al. In vivo absence or inhibition of TRPA1 results in reduced mechanical hypersensitivity in animal models of inflammation Petrus et al. Absence of TRPV1 in vivo reduces inflammation-induced swelling, thermal hypersensitivity and nociceptive behaviour in various pain models Caterina et al.
In naive animals, TRPV1 immunoreactivity is localized in nociceptive primary afferents innervating the knee joint. After inflammation, TRPV1 expression increases not only in primary afferents, but is detected in synoviocytes which secrete lubricating fluid into the synovial space and function as local immune cells Kochukov et al.
Primary afferents are thus not only sensitized by peripheral release of pro-inflammatory cytokines, but are surrounded by cells that produce and release these molecules themselves. Further studies are needed to identify specific receptors and mechanisms underlying the anti-inflammatory and anti-hyperalgesic effects of CBD. Transdermal CBD application was successful in decreasing monoarthritis-associated increases of pro-inflammatory biomarkers in neuronal tissues.
In this study, the expression of CGRP in spinal cord was increased after peripheral inflammation as previously reported Sluka and Westlund, , and was decreased by high doses 6. Like other neuropeptides, CGRP is rapidly transported to nerve terminals for release centrally as well as peripherally where as a potent vasodilator it contributes to neurogenic inflammation Kawasaki et al. Although increases in CGRP are described in DRG after hindpaw inflammation Nahin and Byers, , no significant changes in DRG expression were observed here data not shown , possibly due to the small number of sensory neurons innervating the joint.
It is also plausible that by 7 days post monoarthritis induction, neuropeptide content has stabilized. In monoarthritic animals, spinal cord OX42 expression is increased in activated microglia, the immune cells specific to the central nervous system, as previously described for CFA-induced ankle inflammation and trinitrobenzene sulfonic acid TNBS -induced pancreatitis Shan et al. Treatment with high doses of transdermal CBD in this study effectively reduced OX42 expression below baseline levels, indicating reduced microglial activation.
CBD is a known non-psychoactive cannabinoid, and due to its low affinity for the CB1 receptor it would be expected that exploratory behavioural activity would be similar among treatment groups compared to negative side-effects associated with THC Croxford, ; Malone et al.
This was demonstrated in this study by lack of CBD-induced changes in open-field exploration among naive treatment groups. Combinatorial with psychoactivity, side-effects such as hypothermia and hypomobility induced by THC are avoided with use of CBD Zimmer et al. These studies demonstrate transdermal administration of CBD has long-lasting therapeutic effects without psychoactive side-effects. Thus, use of topical CBD has potential as effective treatment of arthritic symptomatology.
The data presented suggest transdermal CBD is a good candidate for developing improved therapies for these debilitating disease. Stinchcomb, University of Kentucky start-up funds to K.
Westlund and All-Tranz, Inc. Cannabidiol was a generous gift provided by NIDA. National Center for Biotechnology Information , U. Author manuscript; available in PMC Jul 1. Hammell , 1, a L. Zhang , 2, a F. Abshire , 2 S. McIlwrath , 2 A.
Stinchcomb , 1 and K. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Eur J Pain. See other articles in PMC that cite the published article. Abstract Background Current arthritis treatments often have side-effects attributable to active compounds as well as route of administration. Results Measurement of plasma CBD concentration provided by transdermal absorption revealed linearity with 0.
Conclusions These data indicate that topical CBD application has therapeutic potential for relief of arthritis pain-related behaviours and inflammation without evident side-effects. Introduction Almost 50 million Materials and methods 2. Open in a separate window. Conclusion These studies demonstrate transdermal administration of CBD has long-lasting therapeutic effects without psychoactive side-effects.
Cannabinoids and cannabinoid receptors have been studied as potential targets for reducing pain and inflammation associated with osteoarthritis and rheumatoid arthritis. Cannabinoid side-effects vary and depend on several factors like administrated dose, route of administration, etc.
What does this study add? Transdermal cannabidiol CBD gel application has therapeutic potential for relief of arthritic pain-related behaviours and exerts an anti-inflammation property without evident high brain centre psychoactive effects.
Footnotes Conflicts of interest None declared. All authors discussed the results and commented on the manuscript. Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation. Role of ionotropic cannabinoid receptors in peripheral antipain and antihyperalgesia.
Evidence for novel cannabinoid receptors. Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: Results of a randomised controlled trial. Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Cannabinoids, endocannabinoids, and related analogs in inflammation.
Impaired pain and pain sensation in mice lacking the capsaicin receptor. CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Tetrahydrocannabinol inhibition of macrophage nitric oxide production.
Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain.
Tumor necrosis factor inhibitors and infection complications. Therapeutic potential of cannabinoids in CNS disease. Quantitative analysis of synovial membrane inflammation: A comparison between automated and conventional microscopic measurements.
Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Constitutive activity at the cannabinoid CB1 receptor is required for behavioral response to noxious chemical stimulation of TRPV1: Antinociceptive actions of CB1 inverse agonists. Development of TNF inhibitor therapies for the treatment of rheumatoid arthritis.
Prostaglandins Other Lipid Mediat.
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