Animal studies, and self-reports or research in humans, suggest CBD may also help with:
A significant safety concern with CBD is that it is primarily marketed and sold as a supplement, not a medication. Currently, the FDA does not regulate the safety and purity of dietary supplements. So, you cannot be sure that the product you buy has active ingredients at the dose listed on the label. In addition, the product may contain other unknown elements. We also don’t know the most effective therapeutic dose of CBD for any particular medical condition.
The evidence for cannabidiol health benefits
Cannabidiol (CBD) is often covered in the media, and you may see it touted as an add-in booster to your post-workout smoothie or morning coffee. You can even buy a CBD-infused sports bra. But what exactly is CBD? And why is it so popular?
The Farm Bill removed all hemp-derived products, including CBD, from the Controlled Substances Act, which criminalizes the possession of drugs. In essence, this means that CBD is legal if it comes from hemp, but not if it comes from cannabis (marijuana) – even though it is the exact same molecule. Currently, many people obtain CBD online without a medical marijuana license, which is legal in most states.
Is CBD safe?
People taking high doses of CBD may show abnormalities in liver related blood tests. Many non-prescription drugs, such as acetaminophen (Tylenol), have this same effect. So, you should let your doctor know if you are regularly using CBD.
Given the limitations in the biological activity of CBD itself and its natural derivatives and the fact that the biological properties of CBD derivatives depend on their structure, synthetic derivatives are produced that have been designed so that their structure allows direct interaction with components of the redox system or indirectly with molecular targets interacting with these components, including the cannabinoid receptors ( Table 2 ). The derivatives with potential antioxidant and anti-inflammatory effects include, but are not limited to, (+)-CBD derivatives, dihydrocannabidiol and tetrahydrocannabidiol derivatives, and (+)-dihydro-7-hydroxy-CBD . Promising synthetic derivatives that can modulate redox balance and/or inflammation are presented below.
In addition, the pinene dimethoxy-dimethylheptyl-CBD derivative HU-308 [(3R, 4S, 6S)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol] and its enantiomer HU-433 [(3S, 4R, 6R)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol] were shown to have specific agonistic activity for the CB2 receptor ( Table 2 ), and consequently, anti-inflammatory activity in cultured calvarial osteoblasts from C57BL/6J mice . However, it has been found that HU-433 exhibits greater anti-inflammatory activity with poorer CB2 receptor binding affinity ( Table 2 ) . In contrast, HU-308, a CB2 agonist, was found to decrease TNF-α-induced expression of ICAM-1 and VCAM-1 in sinusoidal endothelial cells of human liver tissue . Another CB2 receptor agonist, HU-910 ((1S,4R)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-1-bicyclo[2.2.1]hept-2enyl]methanol)), significantly inhibits the effects of LPS that lead to increased inflammation (assessed by increased TNF-α expression) and increased oxidative stress (assessed by increased levels of 4-HNE and protein carbonyl groups) in mouse Kupffer cells . This suggests that these effects are associated with CB2 receptor activation ( Table 2 ).
Various cell metabolic systems, including the endocannabinoid system, are involved in the regulation of redox balance. Thus, the action of CBD as a phytocannabinoid may support the biological activity of the endocannabinoid system. CBD has recently been shown to modulate the endocannabinoid system activity by increasing anandamide (AEA) levels , which can affect cannabinoids signaling, including their interaction on cannabinoid receptors . However, it is known that the peroxisome proliferator-activated receptor alpha (PPAR-α), for example, activated by endocannabinoids, directly regulates the expression of antioxidant enzymes such as superoxide dismutase by interacting with their promoter regions . Therefore, it is believed that the most important antioxidant activity of CBD, like endocannabinoids, is associated with its effect on receptors. CBD, depending on the concentration, can activate, antagonize or inhibit cannabinoid receptors (CB1 and CB2), as well as ionotropic (TRP) and nuclear (PPAR) receptors ( Figure 4 ) [52,59,60].
CBD is an agonist of the PPARγ receptor, which is a member of the nuclear receptor superfamily of ligand-inducible transcription factors . PPARγ, an ubiquitin E3 ligase, has been shown to interact directly with NFκB. The interaction occurs between the ligand-binding domain of PPARγ and the Rel homology domain region of the p65 subunit of NFκB. Lys48-linked polyubiquitin of the ligand-binding domain of PPARγ is responsible for proteosomal degradation of p65 . In this way, PPARγ participates in the modulation of inflammation by inducing ubiquitination proteosomal degradation of p65, which causes inhibition of pro-inflammatory gene expression, such as cyclooxygenase (COX2) and some pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6, as well as inhibition of NFκB-mediated inflammatory signaling . For this reason, PPARγ agonists can play an anti-inflammatory role by inhibiting the NFκB-mediated transcription of downstream genes . This molecular mechanism is mediated by β-catenin and glycogen synthase kinase 3 beta (GSK-3β). β-catenin attenuates transcription of pro-inflammatory genes by inhibiting NFκB [85,86]. On the other hand, GSK-3β is decreased by PPARγ stimulation .
5. Effects of Synthetic Derivatives of CBD on Receptors
CBD has also been shown to be an inverse agonist of other GPR receptors, including GPR3, GPR6 and GPR12. It reduces β-arestinin 2 levels and cAMP accumulation in amyloid plaque formation in the development of Alzheimer’s disease, in a concentration-dependent manner . In addition, one of the neuropharmacological effects of CBD is its reducing effect on hippocampal synaptosomes mediated by its interaction with GPR3 . It has also been suggested that the effect of CBD on these orphan receptors represents a new therapeutic approach in diseases such as Alzheimer’s disease, Parkinson’s disease, cancer, and infertility .
GPR55, which is strongly expressed in the nervous and immune systems as well as in other tissues, is a G-protein coupled receptor . Activation of GPR55 increases the intracellular level of calcium ions . CBD is a GPR55 antagonist and can modulate neuronal Ca 2+ levels depending on the excitability of cells . CBD antagonism is manifested as an anticonvulsant effect . Because CBD increases endocannabinoid expression, it can also indirectly affect inflammation and redox balance via these molecules . In addition, GPR55 knockout mice have been shown to have high levels of anti-inflammatory interleukins (IL-4, IL-10, and IFN-γ) , while high expression of GPR55 reduces ROS production . Therefore, the organism’s response to CBD depends on whether direct or indirect effects dominate.
In addition to the direct reduction of oxidant levels, CBD also modifies the redox balance by changing the level and activity of antioxidants [19,26]. CBD antioxidant activity begins at the level of protein transcription by activating the redox-sensitive transcription factor referred to as the nuclear erythroid 2-related factor (Nrf2) , which is responsible for the transcription of cytoprotective genes, including antioxidant genes . CBD was found to increase the mRNA level of superoxide dismutase (SOD) and the enzymatic activity of Cu, Zn- and Mn-SOD, which are responsible for the metabolism of superoxide radicals in the mouse model of diabetic cardiomyopathy type I and in human cardiomyocytes treated with 3-nitropropionic acid or streptozotocin . Repeated doses of CBD in inflammatory conditions were found to increase the activity of glutathione peroxidase and reductase, resulting in a decrease in malonaldehyde (MDA) levels, which were six times higher in untreated controls . Glutathione peroxidase activity (GSHPx) and glutathione level (GSH) were similarly changed after using CBD to treat UVB irradiated human keratinocytes. The high affinity of CBD for the cysteine and selenocysteine residues of these proteins is a possible explanation for this observation . It is known that under oxidative conditions, alterations in enzymatic activity may be caused by oxidative modifications of proteins, mainly aromatic and sulfur amino acids . It has also been suggested that the reactive CBD metabolite cannabidiol hydroxyquinone reacts covalently with cysteine, forming adducts with, for example, glutathione and cytochrome P450 3A11, and thereby inhibiting their biological activity . In addition, CBD has been found to inhibit tryptophan degradation by reducing indoleamine-2,3-dioxygenase activity . CBD also supports the action of antioxidant enzymes by preventing a reduction in the levels of microelements (e.g., Zn or Sn), which are usually lowered in pathological conditions. These elements are necessary for the biological activity of some proteins, especially enzymes such as superoxide dismutase or glutathione peroxidase .
5.2. GPR Receptors
CBD has been shown to be a weak agonist of the human, mouse, and rat CB1 receptor . The activation of the CB1 receptor increases ROS production and a pro-inflammatory response, including the downstream synthesis of tumor necrosis factor α (TNF-α) . In addition, it was shown that CBD is a negative allosteric modulator of the CB1 receptor . Regardless of the effect on the CB1 receptor, CBD is a weak agonist of the CB2 receptor , but it has also been suggested that it may demonstrate inverse agonism of the CB2 receptor . Importantly, CB2 activation leads to a decrease in ROS and TNF-α levels, which reduces oxidative stress and inflammation . Therefore, it has been suggested that CBD may indirectly improve anti-inflammatory effects. Clinical studies have confirmed that CBD reduces the levels of pro-inflammatory cytokines, inhibits T cell proliferation, induces T cell apoptosis and reduces migration and adhesion of immune cells . In addition, CBD anti-inflammatory activity has been shown to be antagonized by both a selective CB2 antagonist and AEA, an endogenous CB2 receptor agonist .
Relatively recently, multidirectional biological effects have been demonstrated in various preclinical models, including the antioxidant and anti-inflammatory effects of cannabidiol [14,73]. In the context of the above data, CBD seems to be more preferred than other compounds from the phytocannabinoid group. Regardless of the beneficial pharmacological effects of CBD itself, if this compound is present in the Δ 9 -THC environment, the undesirable effects of 99-THC are reduced, which improves its safety profile .