CBD also acts as an agonist for ionotropic cannabinoid receptors including chemo- and thermosensitive members of the TRP channel superfamily (TRPV1, TRPA1, TRPV2, TRPV3, TRPV4) (Fioravanti et al., 2008; Kress and Kuner, 2009). 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., 2000; Szabo et al., 2005; Petrus et al., 2007; Kerstein et al., 2009; Akopian, 2011). 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., 2001; Costa et al., 2004b; Akopian et al., 2008, 2009). In vivo absence or inhibition of TRPA1 results in reduced mechanical hypersensitivity in animal models of inflammation (Petrus et al., 2007; McGaraughty et al., 2010; Akopian, 2011). Absence of TRPV1 in vivo reduces inflammation-induced swelling, thermal hypersensitivity and nociceptive behaviour in various pain models (Caterina et al., 2000; Davis et al., 2000; Keeble et al., 2005; Szabo et al., 2005). 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., 2009). Once activated, synoviocytes release pro-inflammatory cytokines and chemokines such as IL1-α, IL-6, TNFα and RANTES, as well as COX-2 (Guerne et al., 1989; Berckmans et al., 2005; Westlund et al., 2010). Released TNFα not only sensitizes primary afferents (Sorkin and Doom, 2000; Schafers and Sorkin, 2008), but also acts in an autocrine fashion, increasing the expression of TRPV1 in synoviocytes (Kochukov et al., 2009). 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. Release of TNFα from cultured synoviocytes from arthritic animals is reduced by application of CBD (Malfait et al., 2000) as well as by TRPV1 antagonists (Kochukov et al., 2009). Desensitization of TRPV1 by CBD could thus interrupt further progression of this cycle. Further studies are needed to identify specific receptors and mechanisms underlying the anti-inflammatory and anti-hyperalgesic effects of CBD.
Assessment of knee joint inflammation. (A) Ipsilateral knee joint circumference was significantly increased in rats with adjuvant-induced monoarthritis and significantly decreased after four consecutive days of transdermal cannabidiol (CBD) treatment using 6.2 or 62.3 mg/day doses (*p < 0.01; one-way ANOVA). (B) Pain scores (median) were maximal 3 days after adjuvant-induced monoarthritis and were significantly reduced by 6.2 and 62.3 mg/day CBD (*p < 0.05; Kruskal–Wallis test). (C–E) H&E staining of the synovial membrane from (C) a naïve rat, (D) after adjuvant-induced monoarthritis and (E) after adjuvant-induced monoarthritis treated with 6.2 mg/day transdermal CBD. (F) Bar graph shows high doses of CBD (combined 6.2 and 62.3 mg/day doses) reduced synovial membrane thickening more than 50%. (n = 4–7 rats per group) (*p < 0.001; one-way ANOVA).
Quantification of pro-inflammatory biomarkers in the lumbar spinal cord and dorsal root ganglia (DRG). Increases in spinal cord (A) CGRP and (B) OX42 and (C) DRG TNFα after adjuvant-induced monoarthritis are reduced to baseline levels by high doses of transdermal cannabidiol. (n = 4–6 animals per group) (*p < 0.05; one-way ANOVA).
Plasma concentrations (±SD) of CBD in rats with and without complete Freud’s adjuvant (CFA) induction after 4 days treatment with transdermal CBD gel.
4.2 Efficacy of transdermal CBD
Spinal cord sections were stained using monoclonal mouse anti-OX-42 (1:1,000, CD11b/c; Abcam, Cambridge, MA, USA) and rabbit anti-CGRP (1:2000; Bachem, Torrance, CA, USA) antibodies. DRG sections were immunostained with mouse anti-TNFα (1:1000, #52B83; Santa Cruz Biotechnology, Santa Cruz, CA, USA) antibodies. Primary antibodies were detected using the appropriate Alexa Fluor conjugated secondary antibodies (Jackson ImmunoResearch, West Grove, PA, USA). Slides were coverslipped using Vectashield Hard Set mounting medium with DAPI (VectorLabs, Burlingame, CA, USA). Controls included the absence of staining upon omission of the primary antibody and the side to side differences between the ipsilateral and contralateral sides as internal controls.
As a measure of spontaneous pain, limb posture was scored daily in the morning while animals were in their home cages by a scientist blinded to the animal’s treatment. A subjective pain-related behavioural scale was used (Sluka et al., 1993) with 0 – normal; 1 – curling of the toes, 2 – eversion of the paw; 3 – partial weight bearing; 4 – non-weight bearing and guarding and 5 – avoidance of any contact with the hindlimb.
In this study, the expression of CGRP in spinal cord was increased after peripheral inflammation as previously reported (Sluka and Westlund, 1993), and was decreased by high doses (6.2 and 62 mg/day) of transdermal CBD. 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., 1988; Zhang et al., 2001). Although increases in CGRP are described in DRG after hindpaw inflammation (Nahin and Byers, 1994), 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.
The LC/MS system used to analyse samples was comprised of a Waters Alliance 2695 pump, an autosampler, a Micromass ZQ detector and a 996 photodiode array detector with MassLynx software (Milford, MA, USA). A Symmetry ® C18 column (150 × 2.1 mm, 5 μm) with a Sentry Symmetry ® guard column (10 × 2.1 mm, 3.5 μm) was utilized with the LC/MS system. The ZQ detector was used with an electrospray ionization probe set for single ion monitoring for CBD quantification. Analysis was performed in negative mode for m/z 313 [CBD-H]-(dwell time: 0.3 s). Capillary and cone voltage were set at 35 kV and 40 V, respectively. Source block temperature was set at 120 °C, and desolvation temperature to 250 °C. Nitrogen was used as nebulization (flow rate: 50 l/h) and drying gas (flow rate: 450 l/h). The mobile phase was comprised of 75:25 ACN:2 mM ammonium acetate buffer w/5% ACN and used at a flow rate of 0.25 mL/min resulting in a mean CBD retention time of 5.6–5.7 min. Standard curves were linear within the range 2–300 ng/mL and concentrations of samples were determined by comparison.
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. At present, one in five (21%) adults worldwide are diagnosed with some form of arthritis by their physicians (Helmick et al., 2008). The data presented suggest transdermal CBD is a good candidate for developing improved therapies for these debilitating disease.
Muscle spasms, otherwise known as muscle cramps, take place when your muscle(s) involuntarily contracts and remains that way for a period of time, with the individual unable to relax the muscle.
Finally, CBD patches are a smart choice of delivery method for combatting nausea and vomiting. When you are feeling such symptoms the last thing you want to do is drop an earthy liquid under your tongue or swallow a capsule. A CBD patch is far more convenient and provides a consistent stream of relief.
CBD patches use a topical delivery method and this can result in more profound effects.
Using a CBD patch means that the CBD is not broken down by your lungs, liver or digestive system. This means that by the time the CBD enters your bloodstream the majority of the dose is active within your blood and is actually used for therapeutic effects. Whereas, with a CBD oil or CBD tablet, your digestive system breaks a lot of the CBD down and this results in a very small proportion of the CBD advertised actually taking effect and entering your bloodstream.
From the little research that does exist, THC has been found to be more effective in the combatting of nausea and vomiting than CBD. Hence, one should opt for full-spectrum CBD products that contain trace elements of THC (below the legal 0.2% THC limit).
There have been many studies around the world that have proved CBD has therapeutic and medicinal benefits for a wide range of conditions. CBD patches can be used to treat symptoms of an array of conditions. The symptoms that CBD patches may be able to alleviate are listed below. We have included a brief explanation of how exactly CBD can alleviate certain symptoms, while also including links to relevant clinical studies.
One area in which there has in fact been a great deal of interest in terms of clinical research is pain relief. There have certainly been very promising results thus far.