The reduced psychoactivity of CBD-rich cannabis may make it an appealing treatment option for patients seeking anti-inflammatory, anti-pain, anti-anxiety and/or anti-spasm effects without disconcerting euphoria or lethargy.
Cannabidiol (CBD), a non-psychoactive component of the marijuana plant, has generated significant interest among scientists and physicians in recent years. Cannabidiol is a pleiotropic drug that of which produces many effects through multiple molecular pathways. CBD acts through various receptor-independent channels and by binding with a number of non-cannabinoid receptors and ion channels.
Unlike psychoactive THC, CBD has little binding affinity to either the CB1 or CB2 cannabinoid receptors. Instead, CBD indirectly stimulates endogenous cannabinoid signaling by suppressing the enzyme fatty acid amide hydroxylase (FAAH) - the enzyme that breaks down anandamide, the first endocannabinoid discovered in the mammalian brain in 1992.
Whereas the cannabinoid molecules found in cannabis are considered "exogenous ligands" to the cannabinoid (CB) receptor family, anandamide is an "endogenous" cannabinoid ligand - meaning it binds to one or more cannabinoid receptors and is found naturally inside the mammalian brain and body. Anandamide favors the CB1 receptor, which is concentrated in the brain and central nervous system. Because FAAH is involved in the metabolic breakdown of anandamide, less FAAH means more anandamide remains present in the body for a longer duration. More anandamide means greater CB1 activation.
CBD enhances endocannabinoid tone by suppressing FAAH.
By inhibiting the enzyme that metabolizes and degrades anandamide, CBD enhances the body's innate protective endocannabinoid response. At the same time, CBD opposes the action of THC at the CB1 receptor, thereby muting the psychoactive effects of THC. CBD also stimulates the release of 2-AG, another endocannabinoid that activates both CB1 and CB2 receptors. CB2 receptors are predominant in the peripheral nervous system and the immune system.
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The cannabis plant contains dozens of active compounds called cannabinoids, found in various concentrations within a plant's flowers, leaves, and stem. The majority of cannabinoids are located in the flowers of the female plant and are concentrated in a viscous resin, which is produced in glandular structures called 'trichomes'. In addition to its wealth of cannabinoids, the resin is also rich in terpenes. Terpenes are largely responsible for cannabis' distinct odor, as well as much of the variations in physiological effects across strains.
Cannabinoids are delivered to the body via several routes, including through smoking plant material, vaporizing concentrates, ingesting plant material, and topical application. Researchers have identified over 70 unique cannabinoids within the cannabis plant. Many of these cannabinoids interact with the human endocannabinoid system via cannabinoid receptors found throughout our bodies.
Although scientists are still identifying new cannabinoid receptors, research has advanced at a rapid pace. The two main types of cannabinoid receptors in the human body are called CB1 and CB2. The CB1 receptor is expressed mainly in the brain and central nervous system, as well as the lungs, liver and kidneys. The CB2 receptor is primarily expressed in the immune system, hematopoietic cells, and throughout the gut. The affinity of an individual cannabinoid to each receptor, as well as the cannabinoid's own pharmacology, combine to determine how it will affect the human body.
THE MOST COMMON CANNABINOIDS FOUND IN CANNABIS ARE THE FOLLOWING:
THCA - TETRAHYDROCANNABINOLIC ACID
THCA is the main constituent in raw cannabis. THCA converts to Δ9-THC when burned, vaporized, or heated at a certain temperature. THCA, CBDA, CBGA, and other acidic cannabinoids hold the most COX-1 and COX-2 inhibition, contributing to cannabis' anti-inflammatory effects. This cannabinoid also acts as an antiproliferative and antispasmodic.
THC - TETRAHYDROCANNABINOL
The most abundant cannabinoid present in marijuana, THC is responsible for cannabis' most well-known psychoactive effects. THC acts as a partial agonist at the CB1 and CB2 receptors. The compound is a mild analgesic, or painkiller, and cellular research has shown that it has antioxidant activity.
CBDA - CANNABIDIOLIC ACID
CBDA, similar to THCA, is the main constituent in cannabis with elevated CBD levels. CBDA selectively inhibits the COX-2 enzyme, contributing to cannabis' anti-inflammatory effects.
CBN - CANNABINOL
CBN is a mildly psychoactive cannabinoid that is produced from the degradation of THC. There is usually very little to no CBN in a fresh plant. CBN acts as a weak agonist at both the CB1 and CB2 receptors, with greater affinity for CB2 receptors than CB1. The degradation of THC into CBN is often described as creating a sedative effect , known as a "couch lock."
CBG - CANNABIGEROL
A non-psychoactive cannabinoid, CBG's antibacterial effects can alter the overall effects of cannabis. CBG is known to kill or slow bacterial growth, reduce inflammation (particularly in its acidic CBGA form), inhibit cell growth in tumor/cancer cells, and promote bone growth. It acts as a low-affinity antagonist at the CB1 receptor. CBG pharmacological activity at the CB2 receptor is currently unknown.
CBC - CANNABICHROMENE
CBC is most frequently found in tropical cannabis varieties. CBC is known to relieve pain, reduce inflammation, inhibit cell growth in tumor/cancer cells, and promote bone growth. The effects of CBC appear to be mediated through non-cannabinoid receptor interactions.
THCV - TETRAHYDROCANNABIVARIN
THCV is a minor cannabinoid found in only some strains of cannabis. The only structural difference between THCV and THC is the presence of a propyl (3 carbon) group, rather than a pentyl (5 carbon) group, on the molecule. Though this variation may seem subtle, it causes THCV to produce very different effects than THC. These effects include a reduction in panic attacks, suppression of appetite, and the promotion of bone growth. THCV acts as an antagonist at the CB1 receptor and a partial agonist at the CB2 receptor.
CBDV - CANNABIDIVARIN
Like THCV, CBDV differs from CBD only by the substitution of a pentyl (5 carbon) fora propyl (3 carbon) sidechain. Although research on CBDV is still in its initial stages, recent studies have shown promise for its use in the management of epilepsy. This is due to its action at TRPV1 receptors and modulation of gene expression.
Laboratory/Animal/Preclinical Studies on:
One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors. During this 2-year study, groups of mice and rats were given various doses of THC by gavage. A dose-related decrease in the incidence of hepatic adenoma tumors and hepatocellular carcinoma (HCC) was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were also noted in the rats. In another study, delta-9-THC, delta-8-THC, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo . In addition, other tumors have been shown to be sensitive to cannabinoid-induced growth inhibition.[5–8]
Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of tumor angiogenesis invasion and metastasis.[9–12] Two reviews summarize the molecular mechanisms of action of cannabinoids as antitumor agents.[13,14] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. For example, these compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats, while they protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1 receptor.
The effects of delta-9-THC and a synthetic agonist of the CB2 receptor were investigated in HCC. Both agents reduced the viability of HCC cells in vitro and demonstrated antitumor effects in HCC subcutaneous xenografts in nude mice. The investigations documented that the anti-HCC effects are mediated by way of the CB2 receptor. Similar to findings in glioma cells, the cannabinoids were shown to trigger cell death through stimulation of an endoplasmic reticulum stress pathway that activates autophagy and promotes apoptosis. Other investigations have confirmed that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma and breast cancer.
An in vitro study of the effect of CBD on programmed cell death in breast cancer cell lines found that CBD induced programmed cell death, independent of the CB1, CB2, or vanilloid receptors. CBD inhibited the survival of both estrogen receptor–positive and estrogen receptor–negative breast cancer cell lines, inducing apoptosis in a concentration-dependent manner while having little effect on nontumorigenic mammary cells. Other studies have also shown the antitumor effect of cannabinoids (i.e., CBD and THC) in preclinical models of breast cancer.[19,20]
CBD has also been demonstrated to exert a chemopreventive effect in a mouse model of colon cancer. In this experimental system, azoxymethane increased premalignant and malignant lesions in the mouse colon. Animals treated with azoxymethane and CBD concurrently were protected from developing premalignant and malignant lesions. In in vitro experiments involving cell lines, the investigators found that CBD protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation. In a subsequent study, the investigators found that the antiproliferative effect of CBD was counteracted by selective CB1 but not CB2 receptor antagonists, suggesting an involvement of CB1 receptors.
Another investigation into the antitumor effects of CBD examined the role of intercellular adhesion molecule-1 (ICAM-1). ICAM-1 expression has been reported to be negatively correlated with cancer metastasis. In lung cancer cell lines, CBD upregulated ICAM-1, leading to decreased cancer cell invasiveness.
In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines. Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[24,25]
In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation. As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[27–30]
CBD may also enhance uptake of cytotoxic drugs into malignant cells. Activation of the transient receptor potential vanilloid type 2 (TRPV2) has been shown to inhibit proliferation of human glioblastoma multiforme cells and overcome resistance to the chemotherapy agent carmustine. In an in vitro model, CBD increased TRPV2 activation and increased uptake of cytotoxic drugs, leading to apoptosis of glioma cells without affecting normal human astrocytes. This suggests that coadministration of CBD with cytotoxic agents may increase drug uptake and potentiate cell death in human glioma cells. Also, CBD together with THC may enhance the antitumor activity of classic chemotherapeutic drugs such as temozolomide in some mouse models of cancer.[13,32]
Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice. Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.
Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing. CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[36,37]
Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesic opioids has been described.[38–40] One study reported that the efficacy of synthetic CB1- and CB2-receptor agonists were comparable with the efficacy of morphine in a murine model of tumor pain.
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