Furthermore, hydrogenated CBD derivatives such as (+)-dihydrocannabidiol and (+)-tetrahydrocannabidiol have CB1 receptor affinity ( Table 2 ) and show anti-inflammatory effects on the peritoneal cells of C57BL/6 mice and a macrophage cell line. This behavior may suggest that the activation of pro-inflammatory mediators is not directly through the CB1 cannabinoid receptor . Similarly, the (+)-8,9-dihydro-7-hydroxy-CBD derivative (HU-465), which has anti-inflammatory activity, especially at higher concentrations, binds to both CB1 and CB2 receptors, while its (−) enantiomer, (−)-8,9-dihydro-7-hydroxy-CBD (HU-446) has negligible affinity for both CB1 and CB2 receptors ( Table 2 ). However, both HU-465 and HU-446 have been found to exhibit anti-inflammatory activity by inhibiting the release of IL-17 in mouse encephalitogenic T cells (TMOG) .
One of the most noticeable CBD antioxidant effects is the reduction in lipid and protein modifications [25,51]. CBD supplementation has been found to reduce lipid peroxidation, as measured by MDA levels, in mouse hippocampal (HT22) neuronal cells depleted of oxygen and glucose under reperfusion conditions . A reduction in lipid peroxidation following CBD supplementation has also been shown in C57BL/6J mouse liver homogenates, assessed by 4-HNE levels . CBD also protected the brain against oxidative protein damage caused by D-amphetamine in a rat model of mania . On the other hand, CBD induced ubiquitination of the amyloid precursor protein (APP), an indicator of cellular changes in the brain of people with Alzheimer’s disease, when evaluated in human neuroblastoma cells (SHSY5Y APP+ ) . In addition, CBD treatment has recently been shown to exhibit an unusual protective effect by transporting proteins including multidrug-1 resistance protein and cytosol transferases, such as S-glutathione-M1 transferase, prior to modification by lipid peroxidation products. This prevents elevation of 4-HNE and MDA adduct levels in fibroblast cell culture . It was also shown that this phytocannabinoid reduced the level of small molecular αβ-unsaturated aldehydes in the myocardial tissue of Sprague-Dawley rats and mice with diabetic cardiomyopathy, and in the liver of mice from the acute alcohol intoxication model [21,25,32]. Additionally, CBD caused a reduction in the level of PUFA cyclization products, such as isoprostanes, in the cortex of transgenic mice (APPswe/PS1ΔE9) with Alzheimer’s disease . Thus, CBD protects lipids and proteins against oxidative damage by modulating the level of oxidative stress, which participates in cell signaling pathways.
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 ).
Indirect antioxidant and anti-inflammatory effects of CBD (closed arrows indicate inhibition; opened arrows indicate activation.
5.1. CB1/CB2 Receptors
Important in CBD therapeutic applications is the lack of psychotropic effects. Furthermore, this phytocannabinoid is not teratogenic or mutagenic . Until recently, CBD was thought to have only low toxicity to humans and other species , but recent studies indicate an increase in ALT and AST levels after CBD treatment, which disqualifies it as the drug of choice [135,136]. In addition, it has been found that CBD may interfere with the hepatic metabolism of some drugs by inactivating cytochrome P450 3A and P450 2C . Such interactions should be considered when co-administering CBD with other drugs metabolized by above enzymes.
This review summarizes the chemical and biological effects of CBD and its natural and synthetic derivatives. Particular attention was paid to the antioxidant and anti-inflammatory effects of CBD and its derivatives, bearing in mind the possibilities of using this phytocannabinoid to protect against oxidative stress and the consequences associated with oxidative modifications of proteins and lipids. Although CBD demonstrates safety and a good side effect profile in many clinical trials , all of the therapeutic options for CBD discussed in this review are limited in a concentration-dependent manner.
Regardless of the direct effect of CBD on TRP receptors, increasing the level of AEA, as a full TRPV1 agonist, also affects the activation of TRP receptors and negatively regulates the 2-arachidonoylglycerol (2-AG) metabolism . It has been shown that both AEA and 2-AG can be synthesized in the plasma membrane. However, the degradation of phosphatidylinositol by phospholipase C results in the formation of a diacylglycerol precursor, whose hydrolysis (through diacylglycerol lipase activity, DAGL) allows the formation of 2-AG . However, activation of DAGLα and DAGLβ requires GSH. Additionally, these enzymes are sensitive to Ca 2+ ions . TRPV1 agonists, such as capsaicin and AEA, have been shown to inhibit 2-AG synthesis in striatal neurons of C57BL/6 mice by glutathione-dependent pathways, since DAGL is stimulated by GSH . In addition, the interaction between AEA and 2-AG has been shown to disappear after inactivation of TRPV1 channels. This suggests that the negative effect of AEA on 2-AG metabolism can be mimicked by stimulation of TRPV1 channels. Therefore, AEA and 2-AG interactions require redox balance, due to the participation of GSH in 2-AG synthesis. In summary, CBD modifies TRPV1 receptor activation through reducing oxidative stress as well as biosynthesis of 2-AG.
3.5. TRP Receptors
It has been shown that CBD can also affect redox balance and inflammation by modulating mammalian transient receptor potential (TRP) channels [72,73]. CBD activates vanilloid receptors (TRPV), directly or indirectly, by increasing the level of endogenous AEA, which is one of the endogenous TRPV1 agonists . CBD, as a TRPV1 receptor agonist, binds to it and causes desensitization, leading to “paradoxical analgesic activity” similar to that of capsaicin . It has been suggested that there is a relationship between molecular signaling of TRPV1 and oxidative stress  because ROS and lipid peroxidation products can regulate the physiological activity of TRPV1 by oxidizing its thiol groups . Consequently, CBD not only activates TRP through a direct agonist-receptor interaction, but also by lowering the level of oxidative stress. In addition, CBD activates other vanilloid receptors such as TRPV2 and the potential ankarin protein 1 receptor subtype (TRPA1), while antagonizing the TRP-8 receptor (TRPM8) . CBD has also been shown to stimulate calcium ions in transfected HEK-293 cells via TRPV3  and regulate calcium ion homeostasis in immune and inflammatory cells mainly via TRP channels, which is important for proliferation and pro-inflammatory related cytokine secretion . In addition, Ca 2+ ions control the activation of several transcription factors (e.g., NFAT) that regulate the expression of various cytokines, such as IL-2, IL-4 and IFNγ, which affect cellular inflammatory responses .
Due to the range of CBD metabolic effects known to date, interest in the possibility of using this phytocannabinoid is constantly growing. Considering the fact that modifications to the CBD structure may result in an improved therapeutic profile and biological activity, natural CBD derivatives are sought and their therapeutic utility is being evaluated. Therefore, known or potential effects of naturally occurring CBD derivatives are presented. Their activity through membrane receptors is emphasized, which are described in this review as those which under the influence of CBD show antioxidant and/or anti-inflammatory activities.
You can vape a full spectrum CBD, which may get you a bit high, even when using a strain with trace amounts of THC.
CBD itself does not bind to receptors but is thought to work by inducing other components of the cannabinoid system.
A CBD isolate refers to a product that is composed of the CBD compound only and is extracted from the marijuana plant. CBD isolates can be extracted from both hemp and non-hemp species of marijuana. Remember, for it to be federally legal, it must come from the hemp species. In states where medicinal marijuana is legal, you can find CBD isolates in a marijuana dispensary. Additionally, certain CBD isolates are synthetic forms, such as those used in the pharmaceuticals Marinol and Syndros – both FDA approved to relieve chemotherapy-induced nausea and to improve appetite in people with AIDS. 3
How to Buy a CBD Product
7. De Gregorio D, McLaughlin R, Posa L, et al.Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain. 2019;160(1):136-150.
What about all those CBD products you’re seeing in line at the supermarket, the local health food store, and online? The market for CBD has basically exploded in the past few years but is completely unregulated. The CBD you buy may come from hemp or may not. It may contain the amount of CBD it claims or may not. It also may contain more THC than it claims. Welcome to the budding world (pun intended) of medicinal CBD.
Your Body Chemistry Matters
Our body’s endocannabinoid system is composed of three main components:
But it’s not that simple. CBD has been shown to decrease the psychotropic effects of THC, meaning that if a full spectrum extract has a greater ratio of THC to CBD, you won’t necessarily feel so high. Of course, everyone responds differently to marijuana and this will involve a lot of trial and error.