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cbd mechanism of action pain

To assess the effects of CBD and expectancy on acute pain reactivity, the researchers conducted a crossover, balanced placebo study that involved healthy adults aged 18 to 30 years. Participants were given either inactive coconut oil or CBD and were told that they had received either inactive coconut oil or CBD. Participants who received CBD were given 50 mg of pure, hemp-derived CBD sublingually in a 0.3-mL solution.

Exp Clin Psychopharmacol. Published online April 22, 2021. Abstract

A Key Driver of Medical Cannabis Use

“What we found is that CBD and expectancies for receiving CBD, both independently and combined, improve the affective or emotional component of pain,” De Vita said.

Still Hope for CBD in Acute Pain Treatment?

The pain-relieving effects of cannabidiol (CBD) may be linked to its influence on affective processes, new research shows.

Cbd mechanism of action pain

CBD is a substance of great therapeutic potential but is currently very understudied. Human CBD short-term studies illustrate low toxicity and mild adverse effects. However, it is unknown what effects will be caused by “CBD gummies” or “CBD water”, which are increasingly offered by manufactures to a wide audience. CBD’s pharmacology is not as clear as Δ9-THC, where the exact mechanism of action is known. Here, we still have much to learn.

The positive effects of CBD were confirmed many years ago [97,98,99], encouraging clinical trials. CBD was proven to be safe and cause only mild adverse effects in humans (e.g., ataxia, sedation, nausea, headache or decreased appetite) [100,101,102,103]. A transdermal CBD-containing gel in patients with peripheral neuropathic pain mitigated pain, as well as cold and itchy sensations [104]. CBD might be used clinically alone or in combination with other cannabinoids. Epidiolex, a pure CBD containing drug, is indicated for the treatment of seizures associated with Lennox Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients 1 year of age and older. In treatment-resistant epilepsy, CBD reduced seizure frequency in both children and adults [105]. In Lennox-Gestaut syndrome, a rare and severe childhood-onset form of epilepsy, oral CBD reduced seizure frequency and improved patients’ overall conditions but triggered adverse effects (somnolence, decreased appetite, diarrhea; more severe in higher doses groups) [106,107]. CBD has shown similar results for the treatment of Dravet syndrome, a drug-resistant epilepsy that begins during the first year of life. CBD diminished major motor seizures and improved patients’ overall condition [108,109].

Schematic representation of CBD enzyme targets. Width of the edges (lines) represents relative EC/IC50 ranging between 77 and 30,000 nM.

Although isolated earlier [4] than Δ9-THC, CBD has remained a more elusive and poorly studied substance, because CBD itself does not produce typical behavioral cannabimimetic effects, and was thought not to be responsible for psychotropic effects of cannabis [5]. The complicated legal status of CBD, throughout the world, further restricted the research and professional knowledge about the therapeutic potential of this compound. In spite of the limitations, numerous anecdotal findings testify to the therapeutic effects of CBD, including anticonvulsant, antipsychotic, anxiolytic, neuroprotective and sleep-promoting effects, which are further supported by research [6]. Initial clinical evidence suggests that CBD possesses a desirable safety profile [7], while numerous preclinical findings present anti-inflammatory effects of CBD [8,9,10,11,12]. However, the pharmacodynamics of CBD have been difficult to elucidate. Initial reports demonstrated that CBD competes poorly with cannabinoid ligands at the orthosteric site of cannabinoid receptors [13], leading to the conclusion that any action of CBD occurs independent of cannabinoid receptors. Further studies revealed this conclusion as partially true. Indeed, CBD directly interacts with various receptors, enzymes and ion channels; however, it was also shown to directly and indirectly interact with the endocannabinoid system [14].

Supplementary Materials

CBD is a well-tolerated and safe natural compound exerting analgesic effects in various animal models of pain, as well as clinical studies. The referenced studies indicate a positive influence of CBD in treatment for various diseases in both pre-clinical and clinical trials. In the majority of animal studies, CBD has been demonstrated to exert analgesic effects, diminishing hyperalgesia and mechanical/thermal allodynia through various routes of administration. When co-administered with Δ9-THC, CBD may reduce the effective dose and diminish negative side effects of Δ9-THC [68,74]. However, some studies indicate no modulation of Δ9-THC’s effects by CBD [96]. Moreover, CBD has the potential to act in an anti-inflammatory way; however; the effects are unclear. In the inflammatory-related pain modes, some research gives hope for an anti-inflammatory action of CBD, while others have reported opposing results. More detailed research is needed to clarify this effect; however, the inflammatory state is not always negative. In arthritic in vitro studies, CBD promoted chondrocyte and synoviocyte apoptosis but with stronger effects on the inflammatory-activated cells, which may be a positive result that indicates anti-arthritic activity [89,90]. The discussed studies indicate a positive influence of CBD on various diseases; nevertheless, animal studies cannot always be translated into human results. It is also important to remember that there are few to no studies on chronic CBD administration in healthy people. Despite the fact that there are trials on heathy volunteers that demonstrate CBD’s safety and good tolerance, these studies do not examine prolonged use, which is common in chronically ill people. Patients suffering from chronic pain are often forced to take medications continuously for many years; it is not possible to test the effects of CBD on healthy people for such a long time [123,124]. Animal studies with chronic CBD treatment last several weeks, up to several months, which may reflect the prolonged use in people, but the differences could not be excluded. In one animal study, Ignatowska-Jankowska et al. demonstrated that repeated CBD treatment may inhibit specific immunity by reducing T, B, T cytotoxic, and T helper cell numbers, while increasing the number of NK and NKT cells involved in nonspecific antiviral and antitumor immune response [125]. Chronic CBD treatment allows for long-term therapeutic effects to be achieved, without significant side effects or tolerance development. Especially important are prolonged anti-inflammatory effects, which may have an influence more directly on the cause of the pain development and therefore provide long-lasting analgesic effect. Acute CBD treatment may not be sufficient to combat the cause of the pain and provide an effect lasting up to several hours (depending on the disease model, dose and route of administration).

The current state of knowledge has exposed CBD’s mechanism action as distinct from the endocannabinoid system. Studies often present CBD’s effects to be mediated by the serotoninergic 5HT1a receptor (5HT1a), which, similar to cannabinoid receptors, is coupled to the Gi protein. Although CBD’s binding to the orthosteric site of 5HT1a is relatively weak (Ki = 16 mM [21]), 100 nM CBD produced an upward shift in the log concentration response curve of the 5HT1a agonist 8-OH-DPAT that resulted in a statistically significant increase in the Emax [22], suggesting positive allosteric modulation of 5HT1a.

Schematic representation of CBD transporter targets. Width of the edges (lines) represents relative EC/IC50 ranging between 100 and 10,000 nM.

4. Summary

Supplementary materials can be found at https://www.mdpi.com/1422-0067/21/22/8870/s1. Materials include a table summarizing results regarding CBD’s action in pain research and a CSV table containing CBD’s pharmacological data. If you are willing to use the tables for further analysis, please cite this paper.

In preclinical models, CBD exerts an analgesic effect via different routes of administration. In a spontaneous canine OA model, CBD increased dogs’ mobility and reduced pain, while no side effects were observed, Gamble et al. demonstrated increased alkaline phosphatase during CBD treatment [81,86]. In rodent OA models, disease is usually induced by intra-articular (i.a.) sodium monoiodoacetate (MIA) injection. In osteoarthritic rats, i.a. CBD administration dose-dependently decreased the joint afferent firing rate. Moreover, an increase in paw withdrawal threshold and weight bearing were observed. A TRPV1 antagonist, SB-366791, significantly inhibited the analgesic effect of CBD with respect to hind paw withdrawal threshold but did not have a significant effect on weight. CBD also reduced local inflammation by decreasing rolling and adherent leukocytes. The anti-rolling effect of CBD at 30 min was blocked by CB2 and TRPV1 antagonists but not a CB1 antagonist. The anti-adherence effect was blocked only by SB-366791. Prophylactic i.a. CBD administration prevented joint pain development and exerted a neuroprotective effect [87]. In a rat complete Freund’s adjuvant-induced monoarthritic knee joint model, transdermal CBD gel applied for 4 days dose-dependently reduced joint swelling, limb posture scores, synovial membrane thickening and animals’ pain. Furthermore, pro-inflammatory factors (Calcitonin gene-related peptide or OX42) were reduced in spinal cord and dorsal root ganglia (TNFα) [9]. In a murine collagen type II-induced arthritis, daily i.p. or oral CBD administration reduced disease progression and blocked LPS-induced increases in serum TNFα. In vitro culture of synovial cells collected from mice treated with CBD released decreased TNFα compared to cells collected from control animals. In vitro CBD also inhibited the release of reactive oxygen species by Zymosan-stimulated neutrophils [88]. The latest study by Lowin et al. showed that in human in vitro culture of rheumatoid arthritis synovial fibroblasts, CBD increases intracellular calcium levels, reduces cell viability, and IL-6/interleukin 8 (IL-8)/MMP-3 production. A TRPA1, but not TRPV1, antagonist reduced the effects of CBD. The effect was enhanced by TNFα pretreatment, which may suggest that CBD preferentially targets pro-inflammatory (activated) synovial fibroblasts, suggesting potential anti-arthritic activity [89]. Similar results from the work of Winklmayr et al. in an in vitro human chondrocytes culture showed that CBD concentrations greater than 4 μM diminished cell viability and increased caspase 3/7 activity, elevated Ca 2+ and Extracellular signal-regulated kinases 1/2 phosphorylation and enhanced apoptotic cell population. This effect was mediated via the CB1 receptor, since AM251 inhibited Ca 2+ influx and reduced the toxic effects of CBD [90].

Cbd mechanism of action pain

The therapeutic potential of cannabinoids to manage several clinical conditions, including pain, inflammation, sleep disorders, and epilepsy, is finding support through a growing body of evidence. 1 With changes in legislation and attitudes toward the medical use of cannabis, more pharmaceutical companies are exploring the therapeutic use of cannabinoids while prioritizing alternate routes of delivery.

Elucidating the therapeutic mechanism of cannabinoids

This article takes a closer look at the mechanism underlying the clinical efficacy of cannabinoids, and reviews a selection of currently available cannabis-derived therapeutics, which may benefit patients with otherwise difficult-to-treat conditions or who are resistant to traditional pharmacotherapy.

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Understanding the activity of endocannabinoid receptors located throughout the body has helped researchers elucidate the mechanism of action of THC, CBD, and other cannabis-derived therapeutics. This has allowed us to target specific receptors that are involved in controlling pain and mediating the inflammatory pathway.