As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ9-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment.
A syringe loaded with a dose of CBD oil is shown in a research laboratory at Colorado State University in Fort Collins, CO. (Credit: AP Photo/David Zalubowski)
A World Health Organization (WHO) report has found no adverse health outcomes but rather several medical applications for cannabidiol, a.k.a. CBD, despite U.S. federal policy on this cannabinoid chemical.
According to a preliminary WHO report published last month, naturally occurring CBD is safe and well tolerated in humans (and animals), and is not associated with any negative public health effects [PDF].
Experts further stated that CBD, a non-psychoactive chemical found in cannabis, does not induce physical dependence and is “not associated with abuse potential.” The WHO also wrote that, unlike THC, people aren’t getting high off of CBD, either.
“To date, there is no evidence of recreational use of CBD or any public health related problems associated with the use of pure CBD,” they wrote. In fact, evidence suggests that CBD mitigates the effects of THC (whether joyous or panicky), according to this and other reports.
The authors pointed out that research has officially confirmed some positive effects of the chemical, however.
The WHO team determined that CBD has “been demonstrated as an effective treatment for epilepsy” in adults, children, and even animals, and that there’s “preliminary evidence” that CBD could be useful in treating Alzheimer’s disease, cancer, psychosis, Parkinson’s disease, and other serious conditions.
In acknowledgement of these kinds of discoveries in recent years, the report continued, “Several countries have modified their national controls to accommodate CBD as a medicinal product.”
But the U.S., the report noted, isn’t one of them. As a cannabis component, CBD remains classified as a Schedule I controlled substance, meaning it has a “high potential for abuse” in the federal government’s view. Nevertheless, the “unsanctioned medical use” of CBD is fairly common, experts found.
For many CBD users in the U.S., the substance’s mostly unsanctioned and illegal state creates problems, especially as a wave of online (mostly hemp) and store-bought CBD oils and extracts have allowed patients to take the treatment process–and the risks involved in buying unregulated medicine–into their own hands and homes.
While CBD itself is safe and found to be helpful for many users, industry experts have warned that not all cannabis extracts are created equally, purely, or with the same methods of extraction.
And while reports of negative reactions to pure CBD are very few and far between, researchers are able to say that the cannabinoid wouldn’t be to blame alone. “Reported adverse effects may be as a result of drug-drug interactions between CBD and patients’ existing medications,” they noted.
As the cannabis reform nonprofit NORML reported, the WHO is currently considering changing CBD’s place in its own drug scheduling code. In September, NORML submitted written testimony to the U.S. Food and Drug Administration (FDA) opposing the enactment of international restrictions on access to CBD.
The FDA, which has repeatedly declined to update its position on cannabis products despite a large and ever-growing body of evidence on the subject, is one of a number of agencies that will be advising the WHO in its final review of CBD.
Perhaps this time around the FDA will listen, and learn something.
The report was presented by the WHO’s Expert Committee on Drug Dependence, and drafted under the responsibility of the WHO Secretariat, Department of Essential Medicines and Health Products, Teams of Innovation, Access and Use and Policy, Governance and Knowledge.
Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy.
Breast cancer is the second leading cause of cancer-related death in women in the United States (1). Conventional treatment options are often limited by toxicity or acquired resistance, and novel agents are needed. We analyzed the effects of the Cannabis sativa constituent, cannabidiol (CBD), a potent, natural compound with reported activity in breast cancer cell lines, and elucidated its effects on key neoplastic pathways.
CBD belongs to the cannabinoid family, a group of pharmacologically active compounds that bind to specific G-protein–coupled receptors (2). Phytocannabinoids are plant-derived products from Cannabis sativa; endogenous cannabinoids are made in animal and human tissues; and synthetic cannabinoids are laboratory produced. The G-protein–coupled receptor CB1 is found mainly in the brain and nervous system, whereas CB2 is expressed predominantly by immune cells (3). Recent data suggest that some cannabinoids also signal through the vallinoid receptor (4), whereas others may function in a receptor-independent manner (3). Cannabinoids can modulate signaling pathways central to the growth and spread of cancer. They inhibit cell-cycle progression and chemotaxis, and block angiogenesis (5). Recent studies have shown that cannabinoids also induce autophagic cell death (6). Δ9-tetrahydrocannabinol (THC) is one of the best-characterized cannabinoids; however, its therapeutic applications are limited by its psychoactive effects. We focused our work on CBD, a phytocannabinoid devoid of these properties (3).
Although CBD is reportedly effective against various tumors, its molecular mechanism of action is not fully characterized. CBD is cytotoxic to gliomas and inhibits tumor cell migration in vitro (7–9). In addition, CBD induces apoptosis in human leukemia cell lines by activating classical caspase pathways, and enhancing NOX4 and p22 (PHOX) function (10). A recent study reports that CBD inhibits breast cancer growth (11) and downregulates ID1, a regulator of metastasis in breast cancer cell lines (12). Furthermore, CBD, in conjunction with THC, induces programmed cell death (PCD) in glioma cells (13).
PCD, a cell suicide program critical to development and tissue homeostasis, can be classified according to the morphology of a dying cell. Apoptosis is a type I PCD involving caspase activation, phosphotidyl serine inversion and DNA fragmentation (14). More recently, autophagy, a process traditionally considered a survival mechanism, was also implicated as a mode of PCD, when excess de novo–synthesized, double membrane-enclosed vesicles engulf and degrade cellular components (15). The relationship between apoptotic and autophagic death is controversial (16). They may cooperate, coexist, or antagonize each other to balance death versus survival signaling (16). We found that CBD induced both apoptosis and autophagy in breast cancer cells, and evaluated further the effects of CBD on the complex interplay between these 2 types of PCD in breast cancer cell lines. Characterizing more precisely the manner by which CBD kills breast cancer cells will help define the optimal applications of CBD as a cancer therapeutic.
Cannabidiol (CBD), a major nonpsychoactive constituent of cannabis, is considered an antineoplastic agent on the basis of its in vitro and in vivo activity against tumor cells. However, the exact molecular mechanism through which CBD mediates this activity is yet to be elucidated. Here, we have shown CBD-induced cell death of breast cancer cells, independent of cannabinoid and vallinoid receptor activation. Electron microscopy revealed morphologies consistent with the coexistence of autophagy and apoptosis. Western blot analysis confirmed these findings. We showed that CBD induces endoplasmic reticulum stress and, subsequently, inhibits AKT and mTOR signaling as shown by decreased levels of phosphorylated mTOR and 4EBP1, and cyclin D1. Analyzing further the cross-talk between the autophagic and apoptotic signaling pathways, we found that beclin1 plays a central role in the induction of CBD-mediated apoptosis in MDA-MB-231 breast cancer cells. Although CBD enhances the interaction between beclin1 and Vps34, it inhibits the association between beclin1 and Bcl-2. In addition, we showed that CBD reduces mitochondrial membrane potential, triggers the translocation of BID to the mitochondria, the release of cytochrome c to the cytosol, and, ultimately, the activation of the intrinsic apoptotic pathway in breast cancer cells. CBD increased the generation of reactive oxygen species (ROS), and ROS inhibition blocked the induction of apoptosis and autophagy. Our study revealed an intricate interplay between apoptosis and autophagy in CBD-treated breast cancer cells and highlighted the value of continued investigation into the potential use of CBD as an antineoplastic agent.