Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids

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A 2020 peer-reviewed research study entitled "Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis" that was published in the journal Cancers investigated the potential wellness efficacy of the three major families of phytomolecules produced by cannabis and hemp. In this long-form article, the results of this study are analyzed and summarized for students.


Study Background

"In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings," noted the study's authors in the report's abstract.


The scientists explained that cannabis-derived cannabinoids "have been shown to be effective in the treatment of various conditions" and that among these is cancer. "In cancer, the endocannabinoid system [ECS] is altered in numerous types of tumors and can relate to cancer prognosis and disease outcome," reported the study.


"In cancer, the endocannabinoid system [ECS] is altered in numerous types of tumors and can relate to cancer prognosis and disease outcome."

The study noted that cannabinoids display anticancer efficacy "by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumor angiogenesis [growth via creation and differentiation of blood vessels]."


The study reported that the use of cannabinoids in formal and established medical therapies for cancer is currently limited to the treatment of symptoms, including the pain and nausea associated with chemotherapy.


The study stressed that cannabinoids are not the only phytomolecules produced by cannabis that are of potential benefit to health maintenance and, more specifically, cancer patients.


The study stressed that cannabinoids are not the only phytomolecules produced by cannabis that are of potential benefit to health maintenance and, more specifically, cancer patients.

"Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of [the] cannabinoids, terpenes, and flavonoids present in cannabis are explored in this literature review," noted the study.


History of Medical Cannabis

The study provided an educational and insightful brief history of the use of cannabis as medicine in the literature. "Archaeobotanical evidence and written records found in ancient texts of Ayurvedic medicine and the first known Pharmacopoeia 'Shen Nung Pen Ts'ao Ching' describe medical use of cannabis for several thousand years," wrote the study.


"Cannabis use, for religious/spiritual, food, and textile has been documented in written history back to at least the third millennium BC and potentially even earlier by archaeological evidence," explained the scientists.

"Cannabis reached South America in the mid-1500s and North America in the early 1600s," they wrote. "During the development of Western Medicine, a progressive understanding of cannabis properties led to wider medical and recreational consumption in the 20th century until the use of this plant became marginalized and criminalized, largely due to misinformation, which greatly impacted progress regarding the understanding of the medicinal benefits of this plant and its components."


The Endocannabinoid System

The study explained that the human endocannabinoid system (ECS) "is comprised of the main endocannabinoids anandamide and 2-arachidonoylglycerol [2-AG] and cannabinoid receptors CB1 and CB2."


"The human ECS is comprised of the main endocannabinoids anandamide and 2-AG and cannabinoid receptors CB1 and CB2."

The study's authors provided additional detail to help clarify the functional components of the ECS, including enzymes and G protein-coupled receptors and said that these ECS elements "could also contribute to the effects of cannabinoids and are therefore identified as possible targets involving this class of compounds."

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Cannabis for Cancer

The researchers noted that the potential role of the ECS in cancer management has "been discussed in several recent publications." It also described how problems in the ECS (in particular, dysregulation) have been associated with several disease states, including cancer. "This dysregulation can include variation in the expression and/or function of cannabinoid receptors and enzymes, or simply alterations in the concentration of endocannabinoids [like 2-AG and anandamide]."


"The levels of endocannabinoids have also been shown to be dysregulated in malignant [cancer] tissues."

Reported the study: "Dysregulation of cannabinoid receptor levels in malignant tissues has been observed and was associated with poor prognosis for patients with different types of cancer. The levels of endocannabinoids have also been shown to be dysregulated in malignant [cancer] tissues."


The study reported that concentrations of the endocannabinoids 2-AG and anandamide "were increased in colorectal carcinomas when compared with healthy neighboring tissue." It noted that prior research studies about the potential benefits of endocannabinoids for cancer revealed "inhibitory effects" from endocannabinoids with regard to the proliferation of breast cancer and prostate cancer.

The study explained how cannabis may be helpful in delivering relief from some of the adverse side effects of the chemotherapy employed to fight cancer and tumor development, including "pain, nausea, and vomiting."


The study stressed that anti-cancer efficacy is delivered not just by endocannabinoids such as 2-AG and anandamide and phytocannabinoids like CBD and THC, but that flavonoids and terpenes (produced by cannabis, hemp, and tens of thousands of other plant species) also "exhibit cytotoxicity against a variety of cancers."


"Before examining the study data for these two popular cannabinoids for a variety of cancer types, students will benefit from an overview of CBD and THC."

This detailed study examined both CBD and THC for anti-cancer efficacy. Before examining the study data for these two popular cannabinoids for a variety of cancer types, students will benefit from an overview of CBD and THC.


CBD

CBD, or cannabidiol, is a popular cannabinoid produced by both cannabis and hemp that features a dominant efficacy, among others, of reductions in inflammation and anxiety. It delivers no psychoactivity* and, therefore, is often the cannabinoid of choice or those who prefer no psychoactivity or who cannot tolerate it (such as certain job types).


*Some thought leaders argue that CBD does, in fact, deliver psychoactivity (in the form of reduced anxiety.) For this reason, some THC consumers who fear potent doses that could potentially produce increased anxiety and even panic attacks carry an emergency CBD vape pen to mitigate any negative symptoms from THC.

The CBD molecule


The study reported that CBD "binds to a large array of physiological targets within the body’s endocannabinoid system," including CB1 and CB2 receptors. Like THC, CBD is typically administered orally and commonly prepared as an oil. The study noted that the lack of psychoactivity presented by CBD gives it "potential as a therapeutic agent" because it is "more appealing than some other cannabinoids that do possess psychoactive effects, like THC."


The research noted that CBD has "exhibited a multitude of beneficial anti-cancer effects in lung, breast, colon, prostate, melanoma, leukemia, cervical, brain, neuroblastoma, and multiple myeloma cancer cells."


THC

THC, or tetrahydrocannabinol, is one of the major cannabinoids produced by cannabis that has demonstrated anti-cancer efficacy, as well as a range of other potential benefits. The study reported that THC mediates its effect in the brain and central nervous system (CNS) by binding with CB1 receptors. "THC binds and activates CB1 receptors in the CNS, leading to the intoxicating feelings associated with cannabis use," reported the study.

The THC molecule


It added that THC can be administered "via multiple routes, including orally, intravenously, intramuscularly, and inhalation." (See "Cannabis Consumption Avenues" for more information.)

The study noted that the most common avenue of consumption for THC is oral. "Due to its high lipophilicity, [THC] is highly bound by plasma proteins and is readily distributed to vascularized tissues such as the liver, heart, and lungs," reported the scientists.


"Fat tissues have also been shown to be reservoirs for THC accumulation."

The study validated an urban legend that THC can build up in adipose (fat) tissues in the human body. "Fat tissues have also been shown to be reservoirs for THC accumulation," it reported. It also noted that the psychoactive effects of THC has produced "concerns in terms of prescribing THC for medicinal use in cancer patients."


Cannabis for Breast Cancer

"In breast cancer cells, treatment with CBD has been shown to induce apoptosis*," reported the study. One of the prior studies reviewed "demonstrated CBD's ability to inhibit epidermal growth factor (EGF)-induced proliferation, migration, and invasion of breast cancer cells."


*Apoptosis is a genetically programmed mechanism by which certain types of bodily cells, including various types of cancer, basically commit suicide and kill themselves.


"Treatment of 6D breast cancer cells with CBD was able to significantly reduce migration and invasion, promoted the recovery of cell contacts, and reduced the expression of malignant markers," reported the scientists. They noted that CBD was also able to "increase sensitivity to [the] anticancer agents doxorubicin and cisplatin in 6D [breast cancer]."

The study found that THC "inhibited overall [breast cancer] cell growth and proliferation." It also showed that THC "reduced human breast cancer cell proliferation via stimulation of CB2 receptors." This is enlightening considering that many sources have cited THC as binding with only CB1 receptors in the ECS (while CBD can bind with both CB1 and CB2 receptors, as indicated above). The research reported that THC treatment "inhibited the cell cycle progression in breast cancer cells...which was attributed to...induced apoptosis."


THC treatment "inhibited the cell cycle progression in breast cancer cells."

In one study reviewed, it was revealed that THC treatment "was able to reduce tumor growth, as well as the amount and severity of lung metastases."


Cannabis for Lung Cancer

CBD has been shown to kill cancer cells involved in lung cancer (via apoptosis). The study also reported that "several studies using lung cancer cells demonstrated that CBD inhibited invasion and metastasis [by lung cancer cells]."


Investigations into THC for lung cancer have produced mixed results, with some revealing negative efficacy (increased cancer activity), some showing neutral outcomes, and others reporting positive results. One of the studies reviewed by this study "found that THC was able to inhibit tumor growth and lung metastases."

The study reported that "THC-loaded nanoparticles for the treatment of lung cancer caused significant cytotoxicity [cancer cell death] against human and murine lung cancer cells in vitro (in experiments not involving living creatures, such as test tubes and petry dishes) and in vivo (involving living creatures, but not clinical trials involving humans).


Cannabis for Glioma

In glioma cancer cells, treatment with CBD has been shown to inhibit cancer cell reproduction and proliferation and to induce apoptosis. One study reviewed revealed that "CBD exhibited a dose-dependent reduction of cell viability in glioma cells and pure CBD was more effective than CBD as a botanical drug substance."


"CBD exhibited dose-dependent reduction of cell viability in glioma cells and pure CBD was more effective than CBD as a botanical drug substance."

Brain cancer studies involving rodents have revealed that "treatment with CBD was able to inhibit tumor growth, enhance apoptosis, and significantly prolong mouse survival." Another study revealed that a mixture of CBD and Temozolomide was more effective at displaying anti-tumor efficacy when THC was added to the mix at a 1:1 ratio with the CBD.


"In neuroblastoma cell lines, CBD decreased [cancer] cell growth, induced cell cycle arrest, reduced invasion, and reduced tumor growth in vivo," reported the study. One of the prior studies it reviewed showed that CBD "induced apoptosis in neuroblastoma cells."

The study found that treatment with THC "produced dose-dependent inhibition of [glioma cancer] cell viability and proliferation and "was able to inhibit [glioma cancer] cell growth."


"In C6 glioma cells, THC exposure increased [cancer] cell death as a result of oxidative stress," reported the researchers. However, they noted that "other studies have shown that human glioma cells were only sensitive to THC at very high, pharmacologically irrelevant concentrations" and that this controversial cannabinoid may actually sometimes display "the potential to stimulate glioma cell growth."


This study reviewed a prior study "[that] demonstrated THC's ability to induce apoptosis in human C6 glioma cells" and suggested that this effect "may be mediated through a CB1 receptor-independent pathway" (mechanisms not involving the CB1 receptor type), indicating that the complex biochemistry of the human ECS involves phytocannabinoids such as THC binding with a number of cellular receptor types and being involved in multiple mechanisms with various outcomes. "Administration of THC also reduced glioma tumor growth in vivo," reported the researchers.


Cannabis for Myeloma

"In multiple myeloma cells," CBD was found to reduce cancer cell viability and to inhibit cancer cell migration.


The study reported that THC has demonstrated "anti-cancer effects in multiple myeloma cells." THC was found to inhibit cancer cell viability and proliferation and to induce the death of myeloma cancer cells. One revealing study showed that "the combination of THC and CBD had the most potent effects in myeloma cells compared to each compound on its own." However, THC treatment alone also reduced migration of myeloma cells.


Cannabis for Pancreatic Cancer

The study noted that, in pancreatic cancers, "cannabinoid receptors have been shown to be much more highly expressed than in regular tissues." THC was shown to be able to potentially "decrease cell viability, induce apoptosis, and reduce the growth of tumors in vivo."


Cannabis for Prostate Cancer

For prostate cancer, CBD has been shown to exhibit "multiple promising anti-cancer effects." The study reported that CBD treatment "was able to significantly reduce the growth of various prostate cancer cell lines." It found that one mechanisms by which CBD inhibits the growth of prostate cancer cells is via apoptosis. It wrote that CBD treatment also inhibited cancerous tumor growth.

In human prostate cancer cells, treatment with THC was "able to reduce [cancer] cell viability." One study reviewed found that "THC induced apoptosis in a dose-dependent and cannabinoid receptor-independent manner in prostate cancer cells."


Cannabis for Colon Cancer

The study revealed that CBD reduced colon cancer cell viability and "promoted apoptosis in colon cancer cells." CBD was also found to reduce the number of tumors in a mouse model of colon cancer. This popular cannabinoid "had a chemo-preventative effect on colon cancer cells." Other studies supported the idea that CBD may reduce "colon cancer cell proliferation [and] induce apoptosis."


"Other studies supported the idea that CBD may reduce "colon cancer cell proliferation [and] induce apoptosis."

"In HCT116 colon cancer cells, CBD's antagonistic activity at [ECS receptor] GPR55 was shown to play a key role in the reduction and prevention of metastasis," reported the study. Other studies revealed that animal models of colorectal cancer "found that CBD treatment induced apoptosis by altering the expression of pro- and anti-apoptotic proteins and decreased overall tumor volume."


Other Cannabinoids

The study also documented the anti-cancer efficacy of a number of other cannabinoids, including CBC, CBDV, CBG, CBN, CBV, and THCV (see citation link to original study below).


Understanding Terpenes

The study explained how the aromatic flavor molecules produced by cannabis and tens of thousands of other plant species called terpenes may contribute to the anti-cancer efficacy that has been observed from cannabinoids such as CBD, CBG, and THC.


"Terpenes may contribute to the anti-cancer efficacy that has been observed in cannabinoids such as CBD, CBG, and THC."

"According to recent publications, 50 cannabis terpenes can be found in North American chemovars, but some are more commonly found," reported the study. The scientists explained how some types (subclasses) of terpenes are difficult to identify, even with advanced laboratory equipment operated by trained technicians.


"In particular, sesquiterpenes are difficult to identify," they wrote while concluding that "the reported terpene profiles of cannabis cultivars may present incomplete portraits of the actual terpenes present in the plant."

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This comprehensive and detailed study examined a number of terpenes for their anti-cancer and medicinal efficacy, including myrcene (the most common terpenes in cannabis and hemp), beta-caryophyllene (BCP), humulene (also produced by the hops used to brew beer), limonene, pinene, linalool, bisabolol, elemene, eucalyptol, borneol, terpineol, nerolidol, guaiol, camphene, and delta-3 carene, among others.


"More than 20,000 terpenes appear in nature, from every plant, flower, and even some insects. Relatively few of these compounds—about 200—are found in cannabis," reported the study.


Individual Terpene Results

The study reported that myrcene has demonstrated "significant cytotoxic effects in various tumors, including breast carcinoma, colon adenocarcinoma, and other [cancer types]." Myrcene also displayed efficacy against "human cervical carcinoma, lung carcinoma, and colon adenocarcinoma."


"The researchers explained how the terpene BCP delivers anti-cancer efficacy for multiple types of cancer, including lung cancer."

The researchers explained how the terpene BCP delivers anti-cancer efficacy for multiple types of cancer, including lung cancer. "β-caryophyllene displayed cytotoxic activity in lung cancer and ovarian cancer cell lines through induction of cell cycle arrest and apoptosis," reported the study.


The study also provided an overview of the medicinal and anti-cancer efficacy of the terpene humulene that is produced by the hops employed to brew beer, which is a plant species cousin of cannabis. It explained how humulene, like myrcene, is one of the most common terpenes produced by cannabis (the two terpenes often appear together and with the terpene BCP).

Humulene-rich hops


"Most cannabis varieties display high levels of the monocyclic sesquiterpene humulene. Humulene, formerly known as α-caryophyllene, is described as one of the core cannabis terpenes along with myrcene, terpinolene, limonene, pinene, and geraniol," reported the scientists.


"Humulene is very common in nature and...responsible for the distinct aroma and flavors of a number of herbs and products," reported the study. "Humulene was first found in the essential oils of Humulus lupulus (common hops), a species of plant in the hemp family that gives beer its distinctive bitter 'hoppy' taste," wrote the study.


"Humulene is very common in nature and...responsible for the distinct aroma and flavors of a number of herbs and products."

The study also described in detail some of the anti-cancer benefits provided by the terpene limonene. "Limonene is a cyclic monoterpene and is the main component of citrus fruit peel oils," reported the scientists. They explained that limonene "exhibits anticancer effects in several types of cancers...by reducing tumor growth and by inducing apoptosis through several mechanisms."

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Limonene was shown to display anti-cancer (cytotoxic) efficacy for bladder cancer, colon cancer ("where d-limonene suppressed cell viability through the induction of apoptosis"), and gastric cancer. In the case of gastric cancer, limonene demonstrated the greatest efficacy when combined with berberine. The study reported that "synergistic anticancer effects were observed" that were not found in either compound alone.


Understanding Flavonoids

The study provided a terse summary of many functional elements of flavonoids, the third family of wellness molecules produced by cannabis and hemp. "Flavonoids are by far the largest class of polyphenols and have been estimated to contain over 8000 metabolites with vast structural and functional diversity," reported the research investigation.


"Flavonoids are by far the largest class of polyphenols and have been estimated to contain over 8000 metabolites."

The study explained that flavonoids have been categorized into six sub-classes, including: Flavones, flavonols, flavanones, flavanols, isoflavones, and anthocyanidi. It explained that the major evolutionary function of flavonoids for the flowers, fruits, and vegetable species that produce them is "vivid color pigmentation" that attracts pollinators (insects and humans) and detracts pests and predators—all in an effort to propagate the species by giving it an opportunity to reproduce.


The study explained that flavonoids compose "roughly 10 percent of [the] compounds known in cannabis."

Unlike cannabinoids and terpenes, flavonoids are not produced in the nearly microscopic trichome glands that predominantly populate the flowers and sugar leaves of cannabis plants during the final stages of flowering, directly before harvest. "The distribution of the flavonoids in the cannabis plant varies; while they are quasi non-existent in seeds and roots, they may represent up to 2.5 percent of cannabis' leaf and flower dry weight," reported the study.


The study noted that flavonoids, as produced by plants other than cannabis, have been studied at length, but that "little is known about their potential effects in regard to their interactions with other compounds present in cannabis."


The study reported that some of the best-known flavonoids are kaempferol and quercetin and that "some are uniquely found in cannabis, such as the cannflavins."


Individual Flavonoid Results

The study reported that kaempferol "is a well-characterized natural flavonol that is commonly found in dietary items like tea, apples, strawberries, broccoli, and beans." It noted that this flavonoid is also produced by cannabis and that much research exists about it, including its anti-cancer potential.


"Treatment with the flavonoid kaempferol inhibited cell viability in a dose-dependent manner in a multitude of cancer subtypes."

"Kaempferol treatment inhibited cell viability in a dose-dependent manner in a multitude of cancer subtypes," reported the scientists. "Most of the studies reviewed indicated that kaempferol's inhibitory effects on the viability of cancer cells were as a result of cell cycle arrest or apoptosis," it reported.


The study reported that the anti-cancer efficacy of kaempferol included benefits for a number of cancer types, including breast, leukemia, liver, oral, ovarian, and stomach cancers. "In glioblastoma, hepatic, colorectal, pancreatic, lung, renal, and breast cancer cell lines, kaempferol was able to significantly reduce migration and/or invasion [by cancer cells]," it wrote.

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The study reported that kaempferol is a potential anti-cancer agent for "gastric, colon, prostate, colorectal, and neuroblastoma cancer cells," where this flavonoid has been shown to be able to "significantly decreased [cancer] cell viability and proliferation."


The flavonoid apigenin is a natural flavone produced by "many fruits and vegetables and predominantly found in parsley, celery, and in the flower of chamomile plants," among others. Apigenin produces a yellow pigment.


Like other flavonoids, terpenes, and cannabinoids, this flavonoid has been found to have potential anti-cancer efficacy for a number of types of cancer, including "breast, lung, liver, brain, skin, blood, bone, colon, prostate, pancreatic, cervical, ovarian, oral, and stomach."

Like other flavonoids, terpenes, and cannabinoids, this flavonoid has been found to have potential anti-cancer efficacy for a number of types of cancer, including "breast, lung, liver, brain, skin, blood, bone, colon, prostate, pancreatic, cervical, ovarian, oral, and stomach."


The study found that apigenin, when combined with the chemotherapeutic sorafenib, "decreased cell viability of liver cancer cells to a greater extent than either drug alone."

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The study also reported on prior research that investigated the potential of Cannflavin B derivatives in the treatment of pancreatic cancer. Results showed "an increase in apoptosis in two pancreatic cancer cell lines treated with concentrations of caflanone, the Cannflavin B derivative." Although a bit is known about Cannflavin B's anti-cancer efficacy, the study reported that considerably "little is known about the potential actions of Cannflavin A and Cannflavin C in cancer."


Results showed "an increase in apoptosis in two pancreatic cancer cell lines treated with concentrations of caflanone, the Cannflavin B derivative."

"In 2019, caflanone was granted orphan drug status by the United States Food and Drug Administration and clinical trials with the drug were scheduled to begin as potential treatment for pancreatic cancer," reported the researchers. They added that a source of caflanone has been identified "in a rare, flavonoid-rich cannabis cultivar native to Jamaica known as Black Swan."


Role of the Entourage Effect

The study also covered the controversial and arguably poorly named "entourage effect" (perhaps better labeled the ensemble effect). "It was first suggested by Drs. Mechoulam and Ben-Shabat that the endocannabinoid system demonstrated an effect known as the entourage effect where a multitude of metabolites and related molecules modify the activity of the endogenous cannabinoids anandamide and 2-AG," reported the study.

Pioneering cannabinoid researcher Raphael Mechoulam


The scientists objectively reported that "not everyone is convinced of the existence of this effect." The study explained how critics describe the entourage effect as "a claim with ill-defined and unsubstantiated pharmacological activities that is 'used toward the popularization and sale of ostensible therapeutic products.'"


"In models of breast cancer, a comparison of pure THC and a botanical extract showed that the botanical drug preparation was more potent than pure THC in producing antitumor responses."

"In models of breast cancer, a comparison of pure THC and a botanical extract showed that the botanical drug preparation was more potent than pure THC in producing antitumor responses," reported the study.


Conclusions

The study concluded that many of the cannabinoids, flavonoids, and terpenes present in cannabis "could be part of a therapeutic solution for specific problems found during cancer treatment." It noted that the cannabis herbal plant species offers a number of potential benefits, particularly "in the management of symptoms for patients living with and beyond cancer."


The research encapsulated the potential benefits of cannabis for cancer as predominantly for the treatment of various symptoms of the disease, including "chemotherapy-induced nausea and vomiting, pain, and insomnia." Other studies have also noted the efficacy of cannabinoids and terpenes for the depression and anxiety that frequently accompany a cancer diagnosis.

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The study noted that while cannabis is often less potent than conventional antiemetics (anti-nausea and anti-vomiting agents), "it is sometimes the only drug that works." Cannabis is also, according to this study, the only antiemetic that increases appetite. "The potential of being able to use a single preparation that could hold benefit in the treatment of several adverse effects—instead of multiple prescriptions that might interact with each other or with cancer-directed therapies—seems advantageous."


"Cannabis is also, according to this study, the only antiemetic that increases appetite. However, it is unlikely that consumption of cannabis is sufficient to act as a stand-alone therapy."

The study cautioned readers from positioning cannabis as a panacea or all-encompassing therapeutic treatment for different types of cancers. "It is unlikely that consumption of cannabis is sufficient to act as a stand-alone therapy. Rather, formulations that include compounds present in cannabis could very likely generate the beneficial therapeutic effects needed," they reported.


The study wrapped by stressing the need for additional human clinical trials to reveal the true potential efficacy of cannabis in the treatment of a wide range of types of cancer. "With most of the studies up to now having been done in cell lines or animal models [versus human clinical trials], a lot of work remains, in particular in regard to the bioavailability of these plant-derived compounds, before we fully understand the potential benefits of the cannabis polypharmacy in a way that could be used for the treatment of cancer in humans," it reported.


View the original study.


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