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Cannabinoids as novel anti-inflammatory drugs

Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors. The discovery of Δ 9 -tetrahydrocannabinol (THC) as the major psychoactive principle in marijuana, as well as the identification of cannabinoid receptors and their endogenous ligands, has led to a significant growth in research aimed at understanding the physiological functions of cannabinoids. Cannabinoid receptors include CB1, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of the immune system. Recent studies demonstrated that administration of THC into mice triggered marked apoptosis in T cells and dendritic cells, resulting in immunosuppression. In addition, several studies showed that cannabinoids downregulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immunoregulation. For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endocannabinoids, led to immunosuppression and recovery from immune-mediated injury to organs such as the liver. Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo can constitute a potent treatment modality against inflammatory disorders. This review will focus on the potential use of cannabinoids as a new class of anti-inflammatory agents against a number of inflammatory and autoimmune diseases that are primarily triggered by activated T cells or other cellular immune components.

Cannabis, commonly known as marijuana, is a product of the Cannabis sativa plant and the active compounds from this plant are collectively referred to as cannabinoids. For several centuries, marijuana has been used as an alternative medicine in many cultures and, recently, its beneficial effects have been shown in: the treatment of nausea and vomiting associated with cancer chemotherapy; anorexia and cachexia seen in HIV/AIDS patients; and in neuropathic pain and spasticity in multiple sclerosis [1–4]. Cannabinoid pharmacology has made important advances in recent years after the discovery of the cannabinoid receptors (CB1 and CB2). Cannabinoid receptors and their endogenous ligands have provided an excellent platform for the investigation of the therapeutic effects of cannabinoids. It is well known that CB1 and CB2 are heterotrimeric Gi/o-protein-coupled receptors and that they are both expressed in the periphery and the CNS. However, CB1 expression is predominant in the CNS, especially on presynaptic nerves, and CB2 is primarily expressed on immune cells [5,6].

Arachidonic acid metabolites have been shown to exhibit properties similar to compounds found in Cannabis sativa. These metabolites are hence referred to as endocannabinoids. These ubiquitous endogenous cannabinoids act as natural ligands for the cannabinoid receptors expressed in mammalian tissue, thus constituting an important lipid-signaling system termed the endocannabinoid system. The endocannabinoid system is an important biological regulatory system that has been shown to be highly conserved from lower invertebrates to higher mammals [7]. Other than the lipid transmitters that serve as ligands for the cannabinoid receptors, the endocannabinoid family also comprises the enzymes for biosynthesis and degradation of the ligands. The endocannabinoids include N-arachidonoylethanolamine, anandamide (AEA), 2-arachidonoyl glycerol (2-AG), N-arachydonoyldopamine, noladin ether and virodhamine. AEA was discovered by Devane et al. and is an amide formed from arachidonic acid and ethanolamine [8]. AEA binds to brain CB1 with high affinity and mimics the behavioral actions of exogenous cannabinoid Δ 9 -tetrahydrocannabinol (THC) when injected into rodents. 2-AG was discovered independently 3 years later by Mechoulam et al. [9] and Sugiura et al. [10]. It was found to exist in much higher concentration in serum and brain than AEA. 2-AG has similar affinities for both CB1 and CB2 receptors, as does AEA, but it exhibits higher efficacy. Endocannabinoids are derivatives of arachidonic acid conjugated with either ethanolamine or glycerol. They are synthesized on demand from phospholipid precursors residing in the cell membrane in response to a rise in intracellular calcium levels. Inside cells, endocannabinoids are catalytically hydrolyzed by the aminohydrolase fatty acid amide hydrolase (FAAH), which degrades AEA into arachidonic acid and ethanolamine [11]. 2-AG is hydrolyzed into AEA and glycerol by either FAAH or by monoacyl glycerol lipase (MAGL). Fatty acid-binding proteins (FABPs) have been reported to play an important role as intracellular carriers in the transport of AEA from the plasma membrane to FAAH for their subsequent inactivation [12]. Studies to date indicate that the main pharmacological function of the endocannabinoid system is in neuromodulation: controlling motor functions, cognition, emotional responses, homeostasis and motivation. However, in the periphery, this system is an important modulator of the ANS, immune system and microcirculation [13]. Some well-known natural and synthetic cannabinoids and endocannabinoids are depicted in Table 1 .

Table 1

Selected cannabinoid molecules.

Cannabinoids are potent anti-inflammatory agents and they exert their effects through induction of apoptosis, inhibition of cell proliferation, suppression of cytokine production and induction of T-regulatory cells (Tregs). In this review, we provide an in-depth description of all four different mechanisms and we further discuss the immunosuppressive properties of cannabinoids in the context of inflammatory and autoimmune disease states, triggered by cellular rather than humoral components of the immune system.

Apoptotic effects of cannabinoids on immune cell populations

One major mechanism of immunosupression by cannabinoids is the induction of cell death or apoptosis in immune cell populations. Under normal conditions, apoptosis is required in order to maintain homeostasis and it involves morphological changes (i.e., cell shrinkage, nuclear fragmentation and membrane blebbing) as well as molecular changes (i.e., induction of caspases and cytochrome c leakage) [14]. The extrinsic pathway of apoptosis is initiated with the ligation of death receptors (i.e., CD95) on the cell surface, leading to activation of major caspases, such as caspase 3, 8 and 10. The intrinsic pathway of apoptosis is initiated via mitochondria and caspase 9; cytochrome c and caspase 3 are the major players in the induction of cell death [14,15].

Δ 9 -THC and its apoptotic effects on immune cell populations have been studied extensively: in 1998, Zhu et al. demonstrated that in vitro THC induced apoptosis in murine macrophages and T cells. This study also showed that the process was mediated via activation of Bcl-2 and caspases [16]. It was difficult to demonstrate the apoptotic effects of THC on lymphocytes, in vivo, and our laboratory speculated that this might be due to rapid clearance of dead cells by phagocytic cells. Therefore, we exposed C57BL/6 mice to 10 mg/kg bodyweight THC and, after several time points, (4, 6, 24 and 72 h), obtained lymphocytes from the thymus and spleen of these animals. The cells were incubated for 12–24 h ex vivo and, since the phagocytosis was excluded in the cultures, we detected significant levels of THC-induced apoptosis in T cells, B cells and macrophages [17]. We have also demonstrated that THC induced higher levels of apoptosis in naive lymphocytes, when compared with mitogen-activated lymphocytes, because activated cells downregulated the levels of CB2 on their cell surface [17]. Several studies also reported THC-induced apoptosis in antigen-presenting cells. In bone marrow-derived dendritic cells (DCs), THC induced apoptosis via ligation of both CB1 and CB2 and activation of caspases such as caspase 2, 8 and 9. In vivo, THC administration decreased the number of splenic DCs, as well as MHCII expression by DCs [18,19]. Furthermore, THC increased Bcl-2 and caspase 1 activity in naive and lipopolysaccharide (LPS)-activated macrophages isolated from the peritoneal cavity of mice [16].

Other natural and synthetic cannabinoid compounds (CBD, AEA, ajulemic acid [AjA] and JWH-015), whose structures are depicted in Table 1 , have also been shown to induce apoptosis in murine and human T lymphocytes. Cannabidiol, the nonpsychoactive ingredient in cannabis, induced apoptosis in CD4 + and CD8 + T cells at 4–8-μM concentrations by increasing reactive oxygen species (ROS) production as well as caspase 3 and 8 activity [20].

Ajulemic acid, a side-chain synthetic analog of Δ(8)-THC-11-oic acid, has been shown to induce apoptosis in human peripheral blood T lymphocytes via the intrinsic pathway at concentrations of 1, 3 and 10 μM [21]. In addition, the use of synthetic CB2 agonist JWH-015 treatment in vitro led to cell death via both the death-receptor pathway and the intrinsic pathway. When JWH-015 was administered in vivo, the antigen-specific response to Staphylococcal enterotoxin A was inhibited significantly [22].

It is important to note that, unlike in immune cells, cannabinoids can protect from apoptosis in nontransformed cells of the CNS, which can play a protective role in autoimmune conditions such as multiple sclerosis. Cannabinoids protect against apoptosis of oligodendrocytes via CB1 and CB2 receptors, by signaling through the PI3K/AKT pathway. In vivo and in vitro exposure to arachidonyl-2-ethylamide (ACEA) and WIN55,212-12 protected the cells, while pretreatment with CB1 receptor antagonist SR141716A and CB2 receptor antagonist SR144528 blocked the action of these cannabinoids [23]. In a different study by Jackson et al., 3D mouse brain aggregate cell cultures were compared between wild-type mice and CB1 receptor knockout mice. IFN-γ treatment led to decrease in the neurofilament-H expression in knockout cultures but not in wild-type cultures. In addition, caspase 3 activation was higher in knockout cultures, indicating a protective role of CB1 in neuronal cells [24].

Cannabinoid action on cytokines

Cytokines are the signaling proteins synthesized and secreted by immune cells upon stimulation. They are the modulating factors that balance initiation and resolution of inflammation. One of the possible mechanisms of immune control by cannabinoids during inflammation is the dys-regulation of cytokine production by immune cells and disruption of the well-regulated immune response [25]. Furthermore, cannabinoids may affect immune responses and host resistance by perturbing the balance between the cytokines produced by T-helper subsets, Th1 and Th2. In vitro studies were performed to compare the effect of THC and cannabinol on cytokine production by human T, B, CD8 + , NK and eosinophilic cell lines. However, the results were variable, depending on the cell line and the concentration used [26]. Both pro-inflammatory and anti-inflammatory effects of THC were demonstrated in this study, proposing that different cell populations have varied thresholds of response to cannabinoids. Generally, TNF-α, GM-CSF and IFN-γ levels decreased with drug treatment. Interestingly, while the anti-inflammatory cytokine IL-10 decreased following THC treatment, there was an increase in the proinflammatory cytokine IL-8. In other studies, cannabinoid CP55,940 at nanomolar concentrations was shown to have a stimulatory effect on several cytokines in the human promyelocytic cell line HL-60 [27]. At the molecular level, THC has also been shown to inhibit LPS-stimulated mRNA expression of IL-1α, IL-1β, IL-6 and TNF-α in cultured rat microglial cells; however, the effect was independent of the cannabinoid receptors [28]. In a different study, mice were challenged with Corynebacterium parvum, in vivo, following the administration of the synthetic cannabinoids WIN55,212-2 and HU210. The animals were then challenged with LPS. The results showed decreased levels of TNF-α and IL-12 but increased levels of IL-10 in the serum [29]. This effect was shown to be CB1 receptor dependent.

During chronic inflammation, IL-6 suppression can decrease tissue injury [30]. AjA has been reported to prevent joint-tissue injury in animal models of adjuvant arthritis [31]. Recent studies showed that addition of AjA to human monocyte-derived macrophages in vitro reduced the secretion of IL-6 from activated cells, suggesting that AjA may have a value for treatment of joint inflammation in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and osteoarthritis [32]. It has been observed that the CB2 agonist HU-308 attenuated the hepatic ischemia/reperfusion injury by decreasing the levels of TNF-α, MIP-1α and MIP-2 in the serum and in liver homogenates [33]. Recent in vitro studies have also shown the potent anti-inflammatory effect of synthetic cannabinoids (CP55,940 and WIN55,212-2). Both CP55,940 and WIN55,212-2 downregulated IL-6 and IL-8 cytokine production from IL-1β-stimulated rheumatoid fibroblast-like synoviocytes (FLS), via a non-CB1/CB2-mediated mechanism [34].

Endocannabinoids have also been reported to affect the cytokine biology of various cell systems. Antiproliferative effects of endocannabinoids on cancer cell lines are well established and are discussed in the later section of the review. However, AEA has also been reported to increase cytokine-induced proliferation. Mouse bone marrow cells, when cultured in the presence of IL-3 and AEA, were observed to produce more hematopoietic colonies than with IL-3 alone [35]. Significant suppression of IL-2 expression by 2-AG and the nonhydrolyzable 2-AG ether was observed in leukocytes via activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) [36]. Furthermore, in undifferentiated and macrophage-like differentiated HL-60 cells, 2-AG induced CB2-dependent acceleration in the production of IL-8 [37]. In Theiler’s virus immune-mediated demyelinating disease, inactivation of endocannabinoids through the use of two selective inhibitors of their transport; (R)-N-oleoyl-(1′-hydroxybenzyl)-2′-ethanolamine] (OMDM2) and [(S)-N-oleoyl-(1′-hydroxybenzyl)-2′-ethanolamine (OMDM1) led to decreased production of the proinflammatory cytokines IL-1β and IL-12 [38]. On a contrary note, cytokines have also been shown to affect the endocannabinoid system. IL-12 and IFN-γ have been shown to reduce FAAH activity and protein expression of FAAH, whereas IL-4 or IL-10 stimulated FAAH activity [39]. Table 2 provides a summary of the effect of cannabinoids on cytokines and chemokines in various cell models [26,28,29,32–34,37,40,41].

Table 2

Effect of cannabinoids on cytokine and chemokine production.

Cannabinod Receptor Cell/tissue/serum Effect Ref.
THC ND Macrophage cell line (RAW264.7) Decreases TNF-α [40]
THC ND Peritoneal macrophages Increases IL-1α and IL-1β [41]
THC ND Human cell lines Decreases TNF-α, GM-CSF and IFN-γ, IL-10
Increases IL-8
[26]
THC CB1 and CB2 independent Rat microglial cells Decreases TNF-α, IL-1α, IL-1β and IL-6 [28]
In vivo WIN55,212-2 and HU-210 CB1 dependent Serum Decreases TNF-α, IL-12
Increases IL-10
[29]
Ajulemic acid ND Human synovial monocyte-derived macrophage Decreases IL-6 and IL-1β [32]
HU-308 CB2 dependent Serum and liver homogenates Decreases TNF-α, MIP-1α and MIP-2 [33]
CP55,940 WIN55,212–2 CB1 and CB2 independent Rheumatoid fibroblast-like synoviocytes IL-6 and IL-8 [34]
2-AG CB2 dependent Promyelocytic leukemia cell line (HL-60) Increases IL-8, CXCL8 and CCL2 [37]

AG: Arachidonoylglycerol; CB: Cannabinoid receptor; CCL: CC-chemokine ligand; CXCL8: CXC-chemokine ligand 8; ND: Not determined; THC: Tetrahydrocannabinol.

Cannabinoids & multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disorder that is mediated by myelin-specific self-reactive T cells, macrophages/microglial cells and astrocytes [3,42]. The action of these cells leads to the demyelination of nerve fibers and axons in the CNS of humans and results in many signs and symptoms, such as muscle spasms, tremor, ataxia, weakness or paralysis, constipation and loss of bladder control [42]. There is both anecdotal and clinical evidence to show the effectiveness of cannabinoids in the treatment of MS. In 1994, a survey of 112 MS patients (57 men and 55 women) from the USA and UK was conducted; all of the patients were self-medicating with a form of cannabis. The results of the survey showed that cannabis use improved symptoms such as spasticity, pain, tremor and depression in more than 90% of patients. In eight different clinical studies, MS patients have also reported the benefits of THC (administered via ingestion, inhalation, injection or rectal suppository), cannabis (administered via ingestion or inhalation) and the cannabinoid receptor agonist Nabilone ™ , (administered via ingestion) in treating spasticity, pain, tremor and ataxia [43]. Use of cannabinoids also improved objective test results such as hand-writing tests and bladder control tests [43,44]. In general, cannabinoids are useful in treating MS because they have neuroprotective as well as immunosuppressive properties [44,45]. In this section, we will focus on the latter and discuss the action of endogenous, natural and synthetic cannabinoids on immune cells within the CNS during MS.

The destruction of the blood–brain barrier in MS is initiated by myelin-specific self-reactive T cells. Infiltration of these cells into the spinal cord and CNS, and their subsequent activation, leads to the elimination of the myelin sheath around the nerves and axons [46,47]. The myelin- specific T cells are usually CD4 + , IL-2R + or MHCII-restricted Th1 cells and they secrete proinflammatory cytokines such as IFN-γ and TNF-α [47]. More recently, Th17 cells have been shown to be involved in the pathogenesis of MS [48,49]. One mechanism of immunosuppression by cannabinoids is the induction of apoptosis and Sanchez et al. demonstrated that WIN55,212-2 blocks a passive form of experimental authoimmune encephalomyelitis (EAE) by inducing apoptosis in encephalitogenic cells through partial activation of the CB2 receptor [50]. A CB1-mediated suppressive pathway has also been shown in myelin-specific T cells [24]. This study demonstrated that ex vivo WIN55,212-2 inhibited T-cell recall response to myelin oligodendrocyte glycoprotein (MOG) peptide, as well as decreasing IL-2, IFN-γ and TNF-α production by MOG-activated T cells. Other synthetic cannabinoids, such as JWH-015 and ACEA, also decreased the number of CD4 + infiltrates in the spinal cord of Theiler’s murine encephalomyelitis virus (TMEV)-infected mice [51]. Mestre et al. showed that decreased infiltration of CD4 + T cells upon WIN55,212-2 treatment in EAE mice is due to decreased intercellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1) expression by endothelial cells. Another novel finding of this study demonstrated that WIN55,212-2 exerted its effects by acting through nuclear receptor PPAR-γ [52].

Microglial cells are the macrophages of the CNS and, during MS, they mediate tissue injury in two main ways: antigen presentation and cytokine/chemokine secretion [51,52]. In the initial stages of inflammation, after activation, microglial cells present antigens to myelin-specific T cells, which results in the activation and proliferation of Th1 lineage cells. Arevalo-Martin et al. demonstrated that cannabinoid agonists WIN55,212-2, ACEA or JWH-015 inhibited the activation of microglial cells by TMEV [51]. The investigators confirmed this finding by studying the morphology of the cells (reactive vs resting) as well as by immunohistochemistry. They showed that, after TMEV activation, MHCII molecules co-localized with Mac-1 in the spinal cord sections; however, after 1-day treatment with various cannabinoid agonists, MHCII expression almost disappeared. During this initial stage, co-stimulatory molecule expression, such as that of CD40, also increased and resulted in TNF-α production via the MAPK and JAK/STAT pathways. Ehrhart and colleagues demonstrated that selective stimulation of the CB2 receptor with JWH-015 on murine microglial cells decreased CD40 expression upon IFN-γ activation. This inhibition in CD40 levels translated into decreased JAK/STAT phosphorylation, and decreased TNF-α and nitric oxide production [53].

In the later stages of disease, microglial cells secrete IL-12, IL-13 and IL-23, nitric oxide and glutamate and contribute to myelin sheath destruction. IL-12 drives the proliferation of Th1 cells while IL-23 is important in the maintenance of Th17 cells. A recent study by Correa et al. showed that the endogenous cannabinoid AEA inhibited the expression of IL-12 as well as IL-23 in LPS/IFN-γ-activated human and murine microglia. This inhibition of cytokine production occurred via activation of CB2 and signaling through ERK1/2 and JNK pathways [54]. Palazuelos et al. also showed that the CB2 receptor is involved in myeloid progenitor trafficking, which is necessary for microglia replenishment and activation during MS. Their studies demonstrated that CB2 −/− mice had exacerbated EAE symptoms and CD34 + myeloid progenitor cells had greatly infiltrated into the spinal cords of these animals. As an explanation for the mechanism, they showed that, in the bone marrow, CB2 receptor manipulation with HU-308 increased the expression of chemokines and their receptors (CCL2, CCL3, CCL5, CCR1 and CCR2), which are important in trafficking of progenitor cells into the neuroinflamed tissue [55].

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Cannabinoids also exert their immunosuppressive effects on astrocytes. Astrocytes make up 60–70% of brain cells in the CNS and play important roles in neuronal growth, neuronal signaling, glucose metabolism and glutamate removal [54]. During disease progression, astrocytes are activated to secrete cytokines, chemokines and nitric oxide, thereby contributing to the overall inflammatory response. Because astrocytes express both CB1 and CB2 receptors, several studies investigated the inhibitory role of cannabinoids on this cell population in the context of MS. One study investigated the effects of AEA on TMEV-activated primary murine astrocytes. This study showed that AEA stimulated astrocytes and triggered the production of IL-6 in a CB1-mediated pathway [56]. The precise role of IL-6 in the CNS is still unclear; however, it has been reported that IL-6 secretion potentiates neuronal growth factor production. In addition, IL-6 has been shown to inhibit TNF-α production by IFN-γ/IL-1β-stimulated glial cells [57]. In a different study, Molina-Holgado and coworkers showed that AEA and the synthetic CB1 agonist CP-55940 inhibited nitric oxide production by LPS-stimulated astrocytes isolated from 1-day-old mice in a CB1-dependent manner [23]. In 2005, Sheng et al. demonstrated that human fetal astrocytes express both CB1 and CB2 receptors and that treatment of IL-1β-stimulated astrocytes with WIN55,212-2 decreased inflammatory products including nitric oxide, TNF-α, CXCL10, CCL2 and CCL5 ( Figure 1 ) [54].

The three main cell types that are involved in demyelination of the nerve fibers and axons in the CNS include activated T-cells, microglia and astrocytes. In activated T-cells, treatment with WIN 55,212-12, AEA and JWH-015 has been shown to inhibit cytokine production, infiltration of cells into the spinal cord and in vitro recall response to myelin oligodendrocyte glycoprotein by T-cells. Cannabinoids also inhibit the antigen presenting abilities of microglia by downregulating MHCII expression, costimulatory molecule CD40 expression, as well as cytokine secretion. Astrocytes, the major cell population in the brain, are also affected, as cannabinoid binding to the receptors leads to inhibition of inflammatory molecules, such as nitric oxide, cytokines and chemokines. In addition, anandamide binding leads to secretion of neural growth factor secretion and protection of the neurons in the CNS.

ACEA: Arachidonyl-2-ethylamide; NGF: Neuronal growth factor.

Cannabinoids & colitis

During inflammation, several different cellular pathways are activated in the intestinal tract, leading to a pathological state [58]. Functional CB1 receptor has been shown to be expressed in the human ileum and colon and the number of CB1-expressing cells was found to be significantly increased after inflammation [59,60]. A protective role for these CB1 receptors during inflammation has been shown in a study analyzing the role of the endogenous cannabinoid system in the development of experimental colitis in mice, induced by intrarectal 2,4-dinitrobenzene sulfonic acid (DNBS) treatment or oral dextran sodium sulfate (DSS) administration [59]. The DSS model, originally reported by Okayasu et al., has been used to investigate the role of leukocytes in the development of colitis [61]. Oral administration of 5% DSS in drinking water can induce acute colitis due to chemical injury in the colon. Furthermore, long-term DSS administration produces colorectal carcinoma, which is similar to the dysplasia–carcinoma sequence seen in the course of cancer development in human ulcerative colitis [62]. On the other hand, intestinal inflammation induced by the intrarectal administration of DNBS has many of the characteristic features of Crohn’s disease in humans, involving induction of an IL-12-driven inflammation with a massive Th1-mediated response [63]. The involvement of the endogenous cannabinoid system in the modulation of the acute phase of DNBS-induced colitis was further supported by the increased levels of transcripts coding for CB1 in wild-type mice after induction of inflammation. It was observed that genetic ablation of CB1 receptors rendered mice more sensitive to inflammatory insults. Furthermore, similar to results observed in CB1-deficient mice, pharmacological blockade of CB1 with the specific antagonist SR141716A led to a worsening of colitis [59]. The protective role of the endogenous cannabinoid system was observed 24 h after DNBS treatment and became more evident on days 2 and 3. However, increased spontaneous spiking activity of smooth muscle cell membrane in DNBS-treated colons from CB1 −/− mice was already visible 8 h after DNBS treatment, indicating that inflammation-induced irritation of smooth muscle occurred at an earlier stage than in wild-type mice. This gives further support to the notion that the endogenous cannabinoid system is protective against inflammatory changes. These data indicated that the activation of CB1 and the endogenous cannabinoid system is an early and important physiological step in self-protection of the colon against inflammation.

Pharmacological stimulation of cannabinoid receptors with the potent agonist HU210 also induced a reduction of experimental colitis. It has been reported that cannabinoid receptor stimulation could have a beneficial effect on experimental colitis [64]. Intraperitoneal application of ACEA, a CB1-selective agonist, and JWH-133, a CB2-selective agonist, inhibited oil of mustard (OM)-induced colitis and subsequent symptoms such as induced distal colon weight gain, colon shrinkage, inflammatory damage, diarrhea and histological damage. This study demonstrated a role for CB2 activation in experimental colitis. The fact that both CB1 and CB2 agonists are active in colitis models lends additional support to the theory that signaling through cannabinoid receptors may mediate protective mechanisms in colitis.

In the small intestine, the involvement of CB1 receptors in the control of intestinal motility during croton oil-induced inflammation was recently demonstrated. Izzo et al. showed that pharmacological administration of cannabinoids is able to delay gastrointestinal transit in croton oil-treated mice [65]. It was further suggested that increased levels of CB1 receptor expression in inflamed jejuna may contribute to this protective effect. CB1 receptors were shown to modulate gastrointestinal motility during croton oil-induced inflammation in mice.

Fatty acid amide hydrolase is the major enzyme involved in the degradation of several bioactive fatty amides, in particular anandamide [11], and its genetic deletion in mice leads to a strongly decreased ability to degrade this endocannabinoid and an increase of anandamide levels in several tissues [66]. FAAH-deficient mice showed significant protection against DNBS treatment. However, because anandamide is believed to act not only through cannabinoid receptors but also through other targets, including the peripheral vanilloid receptor TRPV1 [67], the decreased inflammation in FAAH −/− mice could also be due to the activation of targets other than cannabinoid receptors.

In conclusion, cannabinoids have been shown to regulate the tissue response to excessive inflammation in the colon, mediated by both dampening smooth-muscular irritation caused by inflammation and suppressing proinflammatory cytokines, thus controlling the cellular pathways leading to inflammatory responses. These results strongly suggest that modulation of the physiological activity of the cannabinoid system during colonic inflammation might be a promising therapeutic tool for the treatment of several diseases characterized by inflammation of the GI tract.

Cannabinoid system & liver injury

During the past few years, awareness of the cannabinoid system in the pathophysiology of liver disease has gained momentum. Both CB1 and CB2 receptors have been shown to be upregulated in the early stages of liver injury [68–72]. Although embryonic liver has been shown to express CB2 receptor mRNA, adult liver hepatocytes and endothelial cells displayed only a faint physiological level of expression of CB1 receptors and were shown to produce low levels of endocannabinoids. CB1 receptors have been found to be upregulated in the vascular endothelium and in myofibroblasts located in fibrotic bands of cirrhotic livers in human and rodents [72]. CB2 receptors are also expressed in myofibroblasts, inflammatory cells and biliary epithelial cells [69]. There has been growing evidence in recent years to suggest that endocannabinoids may regulate the pathophysiology of liver diseases, including both acute forms of hepatic injury, liver fibrosis and cirrhosis. The endocannabinoids are found in low levels in normal liver, which may be due to high levels of expression of FAAH, which is responsible for the breakdown of AEA [11]. The levels of AEA have been shown to increase in the liver and serum during acute hepatitis and fatty liver disease [70]. In fatty liver, the increase in AEA results from decreased ability of FAAH to degrade AEA. Together, the above studies suggest that endocannabinoids and their receptors may play a critical role in regulating liver fibrogenesis; therefore, targeting the cannabinoid receptors may serve as a novel tool to prevent and treat liver injury.

While the mechanisms of inflammatory liver injury are unclear, they are accompanied by infiltration of activated polymorphonuclear leukocytes, activation of Kupffer cells, production of proinflammatory cytokines and generation of ROS. Many recent studies indicated strongly the increased upregulation of the endocannabinoid system during liver diseases involving hepatocyte injury, inflammation, fibrogenesis, hepatic encephalopathy, cirrhotic cardiomyopathy and portal hypertension [73]. The role of hepatic expression of anandamide and 2-AG is apparent in hepatic ischemia-reperfusion (I/R) injury, in which their levels are significantly increased, correlating with the extent of liver damage. Moreover, pretreatment of mice with JWH-133, a CB2 receptor agonist, was shown to decrease the degree of liver tissue injury and inflammatory cell infiltration and decrease serum levels of cytokines, chemokines and adhesion molecules [74]. Furthermore, CB2 −/− receptor mice were shown to develop greater inflammation and I/R-induced liver damage than their wild-type counterparts. The data also highlights the protective role of CB2 receptor activation in the inflammatory response associated with chronic liver diseases such as viral hepatitis and alcoholic or nonalcoholic fatty liver diseases.

Viral hepatitis, alcohol abuse and nonalcoholic fatty liver are some of the conditions that can induce chronic liver injury and inflammation, leading to activation of fibrogenesis as a wound-healing mechanism. However, persistence of fibrogenic stimuli can enhance deposition of the extracellular matrix by hepatic myofibroblasts, thus disrupting normal liver architecture and, ultimately, leading to cirrhosis and liver failure. CB1 and CB2 receptors are shown to be markedly upregulated in cirrhotic human liver samples, demonstrating the impact of endocannabinoids in liver fibrogenesis. In addition, increases in circulating levels of anadamide and hepatic 2-AG have also been reported in cirrhosis and liver fibrosis, respectively [73]. CB2 −/− mice exposed to CCl4 showed enhanced liver fibrosis when compared with wild-type mice, thereby suggesting a protective role for CB2 receptor activation in liver fibrosis. By contrast, activation of CB1 receptors was found to promote profibrotic response [72]. The pharmacological inactivation of CB1 with rimonabant ® (SR141716) results in the reduction of obesity and hepatic steatosis in rodents [75], demonstrating that CB1 and CB2 receptors exert opposite effects on liver fibrosis and further suggesting that endocannabinoid system regulates both pro- and anti-fibrogenic responses in the liver. Further effects of the endocannabinoids have also been shown to be receptor independent. AEA and 2-AG have been shown to induce necrosis and apoptosis, respectively, in activated hepatic stellate cells, through increased generation of ROS [76].

The abuse of cannabis has been shown to promote liver fibrosis in patients with chronic hepatitis C, indicating that cannabinoids may exacerbate liver fibrogenesis and that CB1 receptor antagonists may play a role as anti-fibrosing molecules [71]. However, an alternative explanation could be that marijuana can trigger immunosuppression. For example, CB2 activation in immune cells can trigger apoptosis and this, in turn, can have an immunosuppressive effect in patients with hepatitis C. As such patients require immunocompetent cells to keep hepatitis under control, chronic marijuana abuse may promote fibrogenesis through the activation of CB2 and consequent suppression of antiviral immunity [77].

Endocannabinoids may also regulate liver cirrhosis by acting as mediators of vascular and cardiac functions. Endocannabinoids can trigger vasorelaxation, while an upregulated CB1-mediated cannabinoid tone causes enhanced mesenteric vasodialation leading to portal hypertension [73,75]. A recent in vivo study by Batkai et al. in rats with CCl4-induced cirrhosis, indicated that increased local production of AEA mediated the inhibition of β-adrenergic responsiveness. Further improvement in contractile function of isolated papillary muscles was observed following treatment with AM251, a CB1 receptor antagonist, suggesting therapeutic potential against cirrhotic cardiomyopathy [75].

There are limited, but reliable, data on the neuroprotective role of the endocannabinoid system in hepatic encephalopathy. It has been demonstrated in a murine model that, during fulminant hepatic failure, levels of 2-AG in the brain are elevated, potentially as a response to liver damage. The administration of the CB2 endogenous ligand 2-AG, an antagonist of CB1 receptor SR141716A or an agonist of CB2 receptor HU308, resulted in a marked improvement in neurological score. Thus, influencing the endocannabinoid system with exogenous cannabinoid derivates specific for the CB1 or CB2 receptor may have a beneficial therapeutic effect on neurological dysfunction in liver diseases [78]. Recently, we noted that both exogenous and endogenous cannabinoids protected mice from concanavalin-A (ConA)-induced acute hepatitis, a model that mimics viral or autoimmune hepatitis, in which T cells play a critical role in triggering liver injury. We found that administration of a single dose of THC or anandamide could ameliorate Con-A-induced hepatitis. We found that this effect was mediated through multiple pathways, including suppression of pro-inflammatory cytokines, induction of apoptosis in activated T cells and induction of forkhead helix transcription factor p3(Foxp3) + Treg cells [79]. This overwhelming evidence shows that the cannabinoid system must play a major role in the pathophysiology of various liver diseases and its therapeutic potential should be exploited for the treatment of chronic liver injuries ( Figure 2 ).

5 Best CBD Oil for Pain & Inflammation: 2022 Update

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All in all, CBD oil has many applications that can benefit patients suffering from chronic pain and other debilitating conditions. It is safe, non-addictive, natural, and can be used for a variety of ailments based on what we’ve read in customer reviews and other scientific studies online. Now that you know a little more about CBD oil, we’ll dig deeper into this topic to help you better understand why you should try the best CBD oils for pain & inflammation in 2022.

With millions of users and dozens of brands, it can be difficult to determine who is providing the highest quality CBD oil out there. We’ve compiled a list of the five best CBD oil companies in the industry to help you make an informed decision.

5 Best CBD Oils for Pain & Inflammation in 2022

We didn’t create this top 5 list lightly. There are many factors that went into choosing these top 5 best CBD oils for pain & inflammation in 2022. If you’re curious how we came to the conclusion that the above brands are the best CBD oil for pain & inflammation, then continue reading below for what helped us determine the best options.

Testimony from Experts

We searched high and low for expert testimonials from CBD oil users. We used these testimonies as part of our decision-making process to choose only the best CBD oils for pain & inflammation this year.

Product Reviews

We looked at dozens of product reviews from popular CBD oil review websites like High Times, Consumer Lab reviews, and CBD Insider reviews. This helped us determine the best products out there.

Price

The next factor we took into consideration was the price. If you’re on a budget or simply looking to make your dollar stretch as far as it can, then you need to know which CBD oil brands offer the best value for your money.

Customer Support

No matter how great a company’s products are, there will always be people who have less-than-positive things to say about them. So we took customer service into consideration when creating our top 5 list of the best CBD oils for pain & inflammation.

Brand Audits

We also conducted a thorough brand audit on each CBD oil brand to determine their reputation in the cannabis industry.

Product Testing

We put in hours of research and testing to determine which CBD oil brands consistently produced the highest quality products. We also looked at product taste, texture, consistency, potency, and ease of use.

When you’re dealing with a chronic pain condition like arthritis or lupus, it can be difficult to find relief from your symptoms. The best CBD oils for pain & inflammation in 2022 can help relieve some of your pain and give you a better quality of life.

1. Colorado Botanicals

Image courtesy Colorado Botanicals

Colorado Botanicals is a top CBD oil for pain & inflammation in 2022 and offers some impressive products. Their CBD oil has no THC (the compound responsible for getting “high” from smoking weed) and their hemp plants are grown without pesticides.

All Colorado Botanicals’ products are non-GMO, vegan friendly, and tested by third-party laboratories to ensure safety. The company uses CO2 extraction when making its CBD oil to maximize potency and purity. This method also preserves all the terpenes in the hemp, which is beneficial for your health and can enhance the quality of sleep.

Colorado Botanicals’ CBD oil comes in a variety of strengths such as 150mg, 750mg, or 1,500mg per bottle. The best part is that the company offers free shipping on all orders over $74 across the United States.

2. Penguin CBD

Image courtesy Penguin CBD

Whether you like penguins or not, we’re confident this is by far the best CBD oil for pain and inflammation in 2022. Also, if you don’t like penguins then you should start liking them right this minute.

All joking aside, Penguin CBD does offer a variety of options to get your daily CBD oil intake. You can take their oil in a capsule or add it to your morning smoothie. They also offer a 1,000mg CBD oil bottle, which provides around 70 servings.

The company offers a 100% satisfaction guarantee on all of its products and has been reviewed by hundreds of customers online. If 1,000mg of CBD oil seems a little too much, Penguin CBD has other strengths such as their 250mg, and 500mg bottles of CBD oil. Their CBD oil bottle goes up to 5,000mg for all you long-term users out there.

3. R+R Medicinals

Image courtesy R+R Medicinals

R+R Medicinals is another top CBD oil for pain & inflammation in 2022. This company offers two varieties of full-spectrum CBD oils, including a 1,000mg version and a 2,000mg. We recommend going with the larger dosage if you’re going through severe pain or have a lot of daily stress that needs relief.

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R+R Medicinals’ CBD oil is non-GMO and is also vegan and gluten free. The company uses coconut MCTs to enhance the bioavailability and absorption of CBD oil.

All of R+R Medicinals products are lab-tested for purity, potency, and consistency. The company offers a money back guarantee on all its products to ensure customer satisfaction. As an added bonus, they offer free shipping on all domestic orders.

4. BATCH CBD

Image courtesy Batch CBD

BATCH CBD is a hemp-derived CBD oil that comes in five different strengths ranging from 250mg to 5,000mg. The company offers one of the strongest lines of products on the market with their 10,000mg version containing up to 50% CBD concentration.

BATCH CBD uses CO2 extraction when making its full-spectrum CBD oil to preserve all the beneficial terpenes found in hemp. BATCH CBD’s non-GMO, vegan friendly oils are free of pesticides and herbicides and are 100% THC FREE.

BATCH CBD offers a money back guarantee on their products. Plus they offer free shipping on orders over $15 across the US.

5. Verma Farms

Image courtesy Verma Farms

Our next CBD oil for pain & inflammation in 2022 is Verma Farms. This company specializes in CBD oil for pain relief, anxiety, depression, chronic fatigue syndrome (CFS), and more. Plus their products can be used by both humans and pets. Their unique tincture allows the product to absorb under the tongue for quick results.

Verma Farms offers a variety of CBD oil products including pet treats, tinctures, and salves. Their full-spectrum hemp oil is made from organically grown hemp plants that don’t require any pesticides or herbicides to grow. Plus they have a guaranteed 3rd party laboratory test on each product, so you know exactly what you’re getting.

Verma Farms’ organic oils are free of pesticides and synthetic fertilizers, so you can rest assured that what you’re ingesting is 100% natural. To reduce the chance of any negative side effects, Verma Farms recommends starting with a low dose first.

6. Bonus: cbdMD

Image courtesy cbdMD

Last, but not least for oil for pain & inflammation in 2022 is cbdMD. They offer full-spectrum CBD oils and come highly recommended by thousands of customers online.

cbdMD’s line of products includes soft gels, topical salves, and oral tinctures that you can take sublingually. Find them at your local vitamin store. The company promises the best quality CBD oils around, with an emphasis on getting their products tested by third-party laboratories to ensure potency and purity.

cbdMD offers a variety of full-spectrum oil for pain & inflammation in 2022 products including 1,000mg, 2,500mg, 5,000mg, or 10,000mg per bottle. Plus they have a full line of pet products for your furry friends in need of pain relief.

But wait, there’s more! We didn’t want to leave you with just the 5 best CBD oils for pain & inflammation in 2022, rather we just had to give you a couple of BONUS options to choose from .

7. Bonus: TheraOne

Image courtesy TheraOne

TheraOne is our second bonus for this list of the best CBD oils for pain & inflammation in 2022. They offer a range of CBD oil tinctures with different CBD concentrations. TheraOne’s CBD is made from 100% organically grown industrial hemp in Colorado.

TheraOne uses an organic extraction process to make its CBD oil, so it’s non-GMO and vegan friendly. Plus they offer a money back guarantee on their products to ensure customer satisfaction.

CBD oil is a natural and non-intoxicating substance that can be extracted from the cannabis plant. CBD oils contain concentrated cannabidiol, which when administered orally or through an inhaler, helps alleviate pain and inflammation.

CBD is one of over 100 cannabinoids present in cannabis plants, but unlike THC (the cannabinoid responsible for getting people “high”), it does not produce any psychoactive effects. In fact, CBD has been shown to actually counteract some of the psychotic symptoms caused by THC exposure.

This makes it a useful therapeutic option for patients with severe forms of epilepsy who find relief from their seizures only when given CBD treatments alongside traditional anticonvulsant medications. It also helps relieve chronic pain without causing cognitive or psychoactive side effects.

CBD is also known to be useful in reducing muscle spasms and fighting certain autoimmune diseases. Its anti-inflammatory properties can help sufferers of arthritis reduce inflammation and ease their joint pain. Scientists believe it may also be effective at suppressing the growth of cancer cells.

In addition to being a health-boosting supplement, CBD has been found to have properties that can be used for cosmetic purposes as well. It moisturizes the skin and helps restore calmness in people who suffer from acne flare-ups. Since it helps treat psoriasis and eczema, CBD is also effective at combating dry skin and minimizing the appearance of fine lines.

CBD is a safe, non-addictive substance that can be used to alleviate aches and pains without causing any negative side effects. Patients have found it to be more effective at treating chronic pain than prescription painkillers, which are known to cause more severe withdrawal symptoms.

In addition to being an effective painkiller, it is also known to be a potent anti-inflammatory and can even reduce seizures caused by epilepsy. It works well on its own but has also shown positive results when it’s used in conjunction with traditional treatments for various different health conditions.

Not only can CBD oils help with pain & inflammation in 2022, but CBD products can help soothe skin disorders such as psoriasis, eczema, and acne flare-ups, as well as relieve symptoms of autoimmune diseases. CBD is also effective at minimizing the appearance of lines and wrinkles without causing any psychoactive side effects or cognitive impairment associated with THC.

What is CBD Oil?

CBD stands for Cannabidiol. It’s one of the many chemical compounds found within marijuana known as cannabinoids, which are also found in other agricultural hemp products like hemp seeds and hemp oil. Cannabis is actually a combination of three distinct plants – cannabis sativa, cannabis indica, and a third lesser known plant called cannabis ruderalis.

CBD Oil is not psychoactive because it does not contain tetrahydrocannabinol (THC), which is the main compound responsible for the “high” that comes from smoking marijuana. However, CBD oil can be infused into different types of food, including candy, honey, gummies, and chocolate.

There are many benefits claimed for CBD oil. Some of these include helping with multiple sclerosis symptoms, treating chronic pain and inflammation, treating mental health conditions like stress and anxiety, fighting acne due to its anti-inflammatory properties, helping cancer patients with nausea and loss of appetite, improving heart health, and promoting better REM sleep.

Many people claim that CBD oil can be used as a natural pain reliever, antidepressant, stress reducer, and even as a potential cancer treatment. However, there aren’t many scientific research studies that back up these claims and the FDA has not approved the use of CBD oil for any medical condition. Currently, CBD oil is used as a food supplement that can be easily purchased online or from most health stores.

What’s the Difference Between CBD Oil and Hemp Seed Oil?

CBD oils made from hemp plants are rich in omega-3 fatty acids, other fatty acids that act as binding agents to help your body absorb more cannabinoids, other plant compounds such as terpenes, and vitamin E.

Hemp seed oil doesn’t contain CBD and is instead extracted from the seeds of hemp plants. This product has a higher ratio of omega-6 to omega-3 fatty acids than its CBD oil counterpart.

Hemp seed oil also contains high levels of the antioxidant compound vitamin E, but little cannabidiol. Hemp seed oil is best suited to cooking or topical applications.

Is CBD Oil Legal?

CBD oils are legal in all states and territories, provided the products contain less than 0.3 percent THC. As the laws surrounding cannabis continue to change, experts recommend checking the federal laws on cannabis-derived compounds like CBD oil before making any purchases.

Hemp-based CBD oil is legal in most countries worldwide, but THC-free marijuana-derived CBD oil may not be legal in some territories. Customers who want to purchase hemp-derived CBD oils should check their country’s laws before placing an order or traveling across the U.S. border to a different state with stricter laws on such products.

What does CBD oil do?

CBD oil works by activating the body’s serotonin (anti-depressant effect), vanilloid (pain relief), and adenosine (anti-inflammatory effect) receptors, while also antagonizing the CB1 and CB2 cannabinoid receptors. Because of the way CBD oil interacts with the brain’s natural chemistry, it’s said to have more of an effect on relieving chronic pain rather than just masking the symptoms like some pain medications do.

Many experts suggest that you start with a small dosage of CBD oil and remain consistent in taking it every day before you notice any effects. It’s also not recommended to stop taking your blood pressure medication, antidepressants, or anti-inflammatory medications before beginning CBD oil treatment – that could lead to unwanted side effects.

Where can you find CBD Oil?

You’ll have no trouble finding CBD oil online or in most drug stores across the country. However, you should always purchase CBD oil products from reputable companies that can provide you with lab reports. This is important because they will show the levels of potential contaminants like pesticides, which are normally used on hemp crops.

To avoid these impurities, many of the high-quality CBD oil companies use a supercritical CO2 extraction process that does not produce any significant heat and avoids using harsh chemicals that could damage the CBD molecules.

Once you’ve selected a CBD oil product ensure that you read all ingredients carefully to ensure your safety – some products contain a mixture of hemp oil and other essential oils, which could cause a negative reaction to those who are allergic.

What can I expect from using CBD Oil?

Because CBD oil has only been recently introduced, there aren’t many studies regarding the long-term effects of taking it. However, some individuals have reported feeling lightheaded or having an upset stomach when they first begin using CBD oil.

Some users have also noticed that they become drowsy shortly after taking their dosage, but this is a common side effect of most prescription painkillers like morphine and oxycodone as well.

There are reports of some users suffering from chronic anxiety or depression when they first began taking CBD oil, but the effects diminished over time.

There haven’t been any notable side effects reported for CBD oil thus far, but there are several precautions to take into consideration before using it:

Avoid taking CBD oil within a couple of hours of your bedtime – it may disrupt your sleep cycle.

People who have a family or personal history of psychosis should be especially careful about using CBD oil.

Make sure that you test any CBD oil product before ingesting it – some have been known to contain high levels of THC despite labeling itself as “pure CBD.”

Always purchase your CBD products from reputable stores or online merchants.

To be on the safe side, you might want to speak with your doctor before taking CBD oil.

How do you take CBD sublingually?

This is the ultimate guide to CBD oil for pain & inflammation in 2022, but you may have one more question.

How do I take it?

If you are wondering how to use CBD oil for pain management, here’s a quick reference guide.

Simply place your preferred amount of drops under your tongue and hold the liquid there for 60-90 seconds. Then, swallow what’s left in your mouth and enjoy the rest.

You should expect to feel results in about 10 minutes, but like we always say. everyone is different. So it may take a bit longer for you.

Do not eat or drink anything 15 minutes before taking CBD, or do so at your own risk.

CBD is not psychoactive, so you won’t get high even if you take too much at once. But why take the chance? Start with a small amount and increase slowly over time to see how your body reacts.

What are the effects of CBD oil under the tongue?

CBD oil is a versatile product that can be taken in many different ways.

But when you take supplements under your tongue, it takes directly into the bloodstream through tiny capillaries called arterioles. From there, the cannabinoids are transported immediately to the CB1 and CB2 receptors located in every organ of your body.

Constantly recycling, these receptors are responsible for the effects of CBD. They affect pleasure, pain, relaxation, and many other functions that keep your body running smoothly.

CBD has been shown to help with.

Relieving pain and inflammation

CBD oil is a natural anti-inflammatory. It’s known for reducing the intensity of chronic pain as well as several inflammatory diseases, including arthritis.

Easing an anxious mind

If you suffer from anxiety, it can be hard to relax, focus, and sleep. Taking CBD oil for anxiety can help you feel calmer and more relaxed throughout the day.

Promoting healthy cell growth

CBD also has antioxidant properties that slow down the aging process, prevent disease and protect your cells from damage. It even helps with acne by inhibiting bacteria responsible for breakouts.

Fighting nausea and vomiting

If you experience chronic nausea or find yourself throwing up often, CBD oil can help. It’s known to ease stomach pain and regulate your digestive tract.

CBD oil is also becoming more popular for treating conditions like migraines, epilepsy, diabetes, multiple sclerosis, schizophrenia, and even cancer due to its anti-inflammatory properties.

Complete Guide For The Best CBD Oils for Pain & Inflammation in 2022

Now that you know the top 5 brands plus two bonus companies to get your CBD oil from, we wanted to share more about how these work to help you with pain and inflammation.

As always, we want you to consult with your doctor about whether these are safe for you to take. As with most medications or supplements, combining CBD oil with prescription medications or other supplements may not have the desired effect. Your doctor will know best if CBD oil is the right option for you.

What Factors Can Cause Pain and Inflammation?

Before we dive too far into the topic of taking any of these recommended CBD oils for pain & inflammation in 2022, we wanted to share more about what factors can cause pain and inflammation to the human body:

Physical Injury

When you suffer a physical injury, it can cause your body to experience pain and inflammation. The injured tissues become stressed during this time because they are trying to heal themselves.

Chemical Stimulation ​

We also have chemical messages in our bodies that can cause us to feel pain or experience inflammation. These molecules are called neurotransmitters, and they manipulate the communication between our cells to produce pain. If these neurotransmitter levels get too high or too low, this can also cause pain and inflammation in your body.

In today’s busy world, it is not surprising to hear that a lot of people suffer from stress on a daily basis. This can cause chemical stimulation, which can lead to inflammation and pain.

Autoimmune Disorders

Unfortunately, some people may suffer from an autoimmune disorder that causes their body to attack itself. When this occurs, it is possible for the person to experience pain and inflammation as their immune system tries to fight off these attacks.

What’s The Best CBD For Pain & Inflammation?

In short, the best CBD oil for pain and inflammation is a product that works to help your body naturally manage these symptoms. They do this by influencing your body’s hormones, neurotransmitters, and immune system functions.

The key here is finding a brand of CBD oil that actually works for you. Take some time to read reviews and inquire with your doctor before you decide on a CBD oil for pain and inflammation.

If you are considering taking CBD oil for any of these conditions or symptoms, we recommend starting slowly at first so that your body can adjust to the effects. Then, gradually increase your dosage as needed until you find what works best for you.

How CBD can potentially help with pain and inflammation

The cells in our body react to pain or injury by releasing chemicals called cytokines. These cytokines signal the immune system to release proteins that cause inflammation, swelling, and other symptoms related to pain.

By taking CBD oil for pain and inflammation, you can help your natural immune response by stopping these signals before they are sent.

CBD oil can also help reduce your body’s production of cytokines, which will help prevent inflammation and swelling. This reduction in cytokine production is another way to manage pain and inflammation that naturally occur in the human body.

By using CBD for pain management you are also reducing the number of chemicals that can cause inflammation in your body. By improving your immune system’s response to inflammation, CBD oil for pain management has the potential to treat many types of chronic pains.

How to Take CBC Oil for Pain

There are numerous ways that you can consume CBD oil. Here is a list of the most popular:

Capsules & Edibles

This is one of the most popular and easiest ways to take CBD oil. Capsules come in a variety of sizes and strengths, depending on how much CBD you need. Many people also enjoy edibles for their convenience and simplicity.

CBD Tincture

A tincture is one of the quickest and easiest ways to incorporate CBD into your daily routine. These products typically come in small glass bottles with a dropper for easy dosing.

Sublingual

A sublingual tincture can be placed under your tongue for fast absorption. This method allows the CBD to travel directly into your bloodstream, making it effective immediately.

Topical Application

Finally, CBD oil can be applied topically for localized relief. Using a topical ointment or cream has many benefits that go beyond pain management. These areas are often where you experience some of your body’s biggest pains, so apply the oil directly here to reduce inflammation and swelling on the spot.

When Should You Take CBD?

If you are taking CBD oil for pain and inflammation, it is best to take your dosage at regular intervals throughout the day. Many people enjoy using their tincture or vape additive first thing in the morning as a way to start their day off on an elevated note.

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Others prefer to use these methods before bed as a way to manage any aches or pains they experienced throughout the day.

What is the Best Dosage for CBD Oil?

The most popular way to take CBD oil is through capsules that are ingested orally. This is the most common dosage for CBD oil, and also the easiest to use if you are not familiar with tinctures.

For acute pain relief, it is best to start at 5-10mg of CBD per day. If this amount does not produce any noticeable changes in your symptoms, then try increasing to 15-25mg.

Lastly, topical ointments and creams should generally be used according to the directions and needs of the user. Topical CBD oil should never be used in place of traditional pain prescriptions.

CBD Oil for Pain: Side Effects & Precautions

While CBD oil is considered very safe, there are a few considerations to keep in mind when taking this or any other supplement. Always buy from a trusted source, and make sure that you are using pure CBD oil with 0% THC.

The use of cannabis is not recommended during pregnancy or while breastfeeding unless absolutely necessary. Furthermore, children should never take CBD oil without the guidance of their doctor.

As always, talk to your doctor before taking any new supplements, especially if you have an existing medical condition.

As CBD is a relatively new supplement, there have not been any long-term studies done on the effects of taking this oil over the course of several years. While it is considered very safe, as with all things you put into your body it’s best to be cautious and informed.

In 2022, the world will know much more about the benefits and uses of CBD oil. As our understanding of this supplement grows, more manufacturers will start making pure CBD products available on a global scale.

While cannabis may still have some legal or social hurdles to overcome in many countries, the use of CBD oil for pain is an exciting and fast-growing market worldwide.

How to Select The Best CBD Oil For Your Pain & Inflammation in 2022

When looking for a CBD oil to help with pain and inflammation, it’s important to select a product that is high quality and has been tested for purity. It’s also important to make sure that the CBD oil has been extracted using a method that allows for fast absorption, such as using carrier oils or vape additives.

It’s best to start with a low dosage of CBD oil and increase gradually if needed until you find the dosage that works best for you. CBD oil can be taken orally, smoked, or applied topically.

There are many ways to take CBD oil, but be sure to follow the directions on your product for optimal results.

As CBD becomes more popular worldwide, manufacturers will develop new products that increase the bioavailability of their capsules or tinctures. This means that you’ll need less CBD oil in each serving size for it to have an impact on your pain and inflammation.

In 2022, CBD oil will most likely remain a popular choice for easing aches and pains due to its fast-acting, long lasting effects. The demand for CBD oil products will likely increase as more states legalize cannabis and consumers look for a safer alternative to opioid painkillers.

Does Taking CBD Get You High?

No! CBD oil products will not get you high, as they contain almost no THC, which is the chemical responsible for the “high” produced by traditional marijuana use.

Even though it is possible to become psychologically addicted to cannabis use, addiction-related to CBD oil use is extremely rare and unlikely.

What is the Difference Between Hemp-Derived vs Marijuana-Derived CBD Oil?

CBD oils made from marijuana plants are also low in THC. But unlike hemp-derived CBD oil, marijuana-derived CBD products may contain more psychoactive compounds like THC, which could induce feelings of sleepiness and euphoria.

Marijuana-derived CBD oil is best for customers who prefer a product with a high THC content or want to experience a “high.”

What Are The Benefits Of CBD Oil?

CBD oil works similarly to other pain medications, but without the unwanted side effects. Though not widely understood by the public, CBD has been found to have many medical benefits, including reducing inflammation and acting as an anti-inflammatory agent itself.

Topical CBD oils are also available for those who want localized relief from arthritis or other inflammatory conditions.

The most common benefits of CBD oil include:

Anti-inflammatory properties that reduce pain and swelling

Fast acting, providing quick relief from chronic or acute disorders

Can be used in conjunction with other therapies to increase the effectiveness of treatment for certain conditions

CBD Oil Legal Status Worldwide

CBD oil is legal throughout much of the world, but it is still considered a controlled substance in many countries.

In some areas of the United States, CBD oil can be purchased at local health food stores. If you live in a state where CBD is not legal, however, you may have to travel outside your city or state to purchase it.

CBD oil can also be purchased online and shipped to customers in most areas of the United States, Canada, and Australia. If you live outside these countries, ask your local health food store about CBD products or find a shop online that can legally ship CBD oils for pain & inflammation in 2022 to your region of the world.

Is Hemp Oil and CBD oil the same?

Hemp oil and CBD oil are not the same, and hemp oil does not contain significant amounts of CBD.

While hemp oil is rich in omega-3 fatty acids and has many health benefits, it’s best known for its ability to improve skin health by hydrating dry, flaky areas such as the elbows and knees – rather than for treating issues such as inflammation and arthritis.

CBD oil is much more potent than hemp oil and does contain high levels of CBD, though it’s worth noting that the other components in cannabis plants, such as THC and terpenes, can also affect your health when combined with CBD.

Different Types of CBD Oil Extracts Are Available

As CBD oil becomes more popular, manufacturers will create new product types with advanced delivery methods to increase bioavailability and reduce negative side effects.

Full Spectrum

As you explore different CBD oil products, you may notice that many are labeled as full spectrum CBD. This means that the extract contains all of the compounds in the hemp plant, including trace amounts of terpenes and cannabinoids such as THC.

Although not to be confused with CBD isolate, full-spectrum CBD does contain small levels of THC to produce the entourage effect.

Because of this, you may experience mild side effects such as feeling tired or groggy after using full-spectrum CBD oil.

Broad Spectrum

Unlike full spectrum oils, pure CBD oil contains only CBD and is free from THC and other trace compounds found in cannabis plants. Since no extra ingredients are added during production, these CBD oils are ideal for customers who prefer the taste of pure oil. There’s also no risk of feeling tired or groggy.

CBD Isolate

CBD oil products labeled as CBD isolate contain 99 percent CBD and less than 0.3 percent THC, making it ideal for those who prefer a pure extract without any additional active compounds.

Efficacy of CBD Oils

CBD oils work best when they contain both omega-3 fatty acids and other fatty acids that act as binding agents to help your body absorb more cannabinoids.

These fatty acids include monounsaturated oleic acid, palmitoleic acid, and stearidonic acid.

The presence of these binding agents makes CBD oil easier for your body to absorb – which means you’ll need smaller doses to experience the same effects as larger amounts of oils with alternative delivery methods.

CBD oils may also contain added terpenes and a wide range of plant extracts designed to enhance bioavailability and produce additional benefits. While many hemp-derived products have high levels of cannabidiol, you should be aware that these ingredients can also contain trace amounts of THC.

Because some CBD products are produced from cannabis plants, the resulting oils may contain small amounts of THC – even if they don’t contain psychoactive ingredients that would produce a “high.” This is fine for most customers who do not have THC allergies or preferences.

Make Use of The Right Dosage Amount

Different CBD oils have different purposes and effects, so it’s best to buy a small amount of CBD oil to determine whether you feel any positive results. It’s also important not to exceed the recommended dosage as too much CBD can be counter-productive.

The dosages for each product vary by manufacturer and range from as little as 20mg per day to up to 1,000mg per day. Refer to the product’s label for specific dosage instructions and information. You can also read reviews from fellow users of CBD oil products, which will provide you with a wider range of experiences and opinions on each product.

What is the Difference Between Hemp-Derived vs Marijuana-Derived CBD Oil?

CBD oils made from marijuana plants are also low in THC. But unlike hemp-derived CBD oil, marijuana-derived CBD products may contain more psychoactive compounds like THC, which could induce feelings of sleepiness and euphoria.

Marijuana-derived CBD oil is best for customers who prefer a product with a high THC content or want to experience a “high.”

What’s the Difference Between CBD Oil and Hemp Seed Oil?

CBD oils made from hemp plants are rich in omega-3 fatty acids, other fatty acids that act as binding agents to help your body absorb more cannabinoids, other plant compounds such as terpenes, and vitamin E.

Hemp seed oil doesn’t contain CBD and is instead extracted from the seeds of hemp plants. This product has a higher ratio of omega-6 to omega-3 fatty acids than its CBD oil counterpart.

Hemp seed oil also contains high levels of the antioxidant compound vitamin E, but little cannabidiol. Hemp seed oil is best suited to cooking or topical applications.

Is CBD Oil Legal?

CBD oils are legal in all states and territories, provided the products contain less than 0.3 percent THC. As the laws surrounding cannabis continue to change, experts recommend checking the federal laws on cannabis-derived compounds like CBD oil before making any purchases.

Hemp-based CBD oil is legal in most countries worldwide, but THC-free marijuana-derived CBD oil may not be legal in some territories. Customers who want to purchase hemp-derived CBD oils should check their country’s laws before placing an order or traveling across the U.S. border to a different state with stricter laws on such products.

What Ingredients Should I Watch Out For in CBD Oils?

The FDA does not regulate CBD oil products. But like other dietary supplements, it recommends consulting with a physician before using any hemp-derived CBD oils to treat medical conditions or to determine dosage amounts.

We also recommend checking the ingredient lists for each product you plan on purchasing at your local store and searching for information about how the product might interfere with other medications you’re taking or how it might interact with existing medical conditions.

In all honesty, if you’re searching for CBD oils for pain & inflammation in 2022 then you’ll want to make sure that there is no more than .3% THC in any of the CBD oils you’re buying. This will ensure you’re less likely to get a “high” from the oils, instead you’ll gain the most out of the medical or therapeutical properties of the CBD oils.

How Can I Find the Best CBD Oil?

CBD oil is gaining more and more recognition every day as a potential treatment for many different ailments. In order to determine which product would be best for you, consider your needs and lifestyle before making any purchase.

CBD oil products are available for purchase online through websites, but customers should have a firm understanding of what to look for before making any purchases.

Research and reviews of CBD oil products are also available through online resources such as the Hemp Business Journal, Leafly, and Project CBD.

How Can I Get Started With CBD Oil?

If you’re considering buying a CBD oil product, the first thing you should do is speak with your doctor to ensure it’s safe for you to use and understand all of the potential benefits of CBD oil.

After speaking with your doctor, you should visit each of the CBD brands’ websites to research more about hemp-derived CBD oils and products available for purchase. Since regulations vary from state to state, make sure to check state laws before making any purchases online.

How do you use CBD oil topically for pain?

CBD oil can be used topically for pain relief in a variety of ways. You can rub CBD oil directly onto the skin where you’re experiencing pain, or you can add it to your favorite lotion or cream to help with absorption.

Another option for using CBD oil topically is to use the CBD oil as a moisturizer or apply it directly to an injury if you’re suffering from joint or muscle pain.

Another reason that people enjoy applying CBD oil topically is because of its soothing effects on the skin and how it can help reduce inflammation. It’s even able to penetrate deep layers of stubborn skin tissue, which can help your muscles and joints better absorb the natural oils.

Each type of CBD oil has its own benefits and offers different possibilities for pain relief. The use, application method, supply, and dosage are all factors that have a bearing on how CBD can help with the pain.

While there are fewer documented cases of side effects from using CBD oil topically, it’s still possible that you could have an allergic reaction or suffer from an unknown irritation while applying CBD oil to affected areas.

Does CBD oil relax muscles?

Many people who use CBD oil and other hemp products believe that the product has a calming effect on the muscles and nerves. While research into how CBD affects connective tissue cells is ongoing, we do know that it interacts at least partially with receptors in the immune system as well as receptors throughout the endocrine and nervous system.

Mast cells make gluten-associated antibodies in response to certain foods like dairy and peanut, which is why some people are highly sensitive to trace amounts of certain foods.

CBD may have a similar effect on mast cells, which can regulate pain and inflammation by stimulating histamine release. By activating or blocking the receptors of neurotransmitters, CBD oil might be able to help reduce inflammation and relax muscles.

How long does it take for CBD oil topicals to work?

The length of time that it takes for CBD oil topicals to start working depends on the application. Creams and lotions will take longer because they need to fully absorb into your skin before you’ll begin to feel their effects, but sublingual tinctures are absorbed into the blood stream almost immediately.

Can I use other pain medications with CBD?

Currently, there aren’t many studies looking at the interaction between CBD and other pain medications. While many people believe that CBD can help relieve some of the pain, it’s important to remember that using any type of new medication without first consulting with your doctor could have serious consequences.

Most doctors will tell you not to mix CBD with other prescription painkillers without first discussing the potential risks. If you’re using both types of medication, ask your doctor if there are any interactions that may be dangerous for your health.

How much CBD should I take?

While it’s possible to take too much CBD oil, the safe upper limit of the product seems to be around 1mg per kilogram of your body weight. While that amount is considered safe for most people, it may still cause problems in smaller or younger individuals.

When taking any type of CBD oil, it’s important to take only the recommended dosage and use the product as directed on the package label. Because everyone’s biochemistry is slightly different, it’s possible that your body may not respond to CBD oil in the same manner as someone else.

If you’re taking any medication other than CBD oil, talk to your doctor about how much CBD you should take and how often you should use it. It’s also important to remember that using other medications with CBD oil may have unexpected consequences.

The same is true of CBD oil and other hemp products such as edibles and extracts, which can alter the effects of either substance on your body when taken together.

CBD seems to be a fairly safe product with few interactions when used properly, but it’s always best to talk to your doctor before beginning to use any new medication or natural remedy.

Recap of the Best CBD Oils for Pain & Inflammation in 2022

Penguin CBD – an extremely popular product that offers excellent value for money.

Verma Farms – another great option that offers full-spectrum CBD oil at a low cost to consumers.

R+R Medicinals – a full-spectrum CBD oil that’s available in the United States and ships to most countries worldwide.

Colorado Botanicals- a popular CBD oil that comes as regular strength and high-potency options.

cbdMD – another popular option that’s available for purchase online but doesn’t ship to Australia.

Bonus: BATCH CBD – a high-quality CBD oil that’s available in nine different strengths.

Bonus: TheraOne – a high-quality CBD oil that’s available in nine different strengths and ships to most countries worldwide.

Final Thoughts

Finally, we hope that you learned a lot of valuable information about how to use CBD oil for pain and inflammation without accidentally getting high from it. We wanted to share more about what factors could potentially cause pain and inflammation to the human body, as well as how CBD oil can be used to help treat these symptoms naturally.

We encourage you to read our other articles to learn more about CBD oil, what it does, how it works, and which brands are the best on the market today. If you have any questions or thoughts for us here, please do feel free to our contact form to reach us.