Cannabidiol in Humans-The Quest for Therapeutic Targets.

“Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties.

However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients.

A systematic search was performed in the electronic databases PubMed and EMBASE using the key word “cannabidiol”. Both monotherapy and combination studies (e.g., CBD + ∆9-THC) were included. A total of 34 studies were identified: 16 of these were experimental studies, conducted in healthy subjects, and 18 were conducted in clinical populations, including multiple sclerosis (six studies), schizophrenia and bipolar mania (four studies), social anxiety disorder (two studies), neuropathic and cancer pain (two studies), cancer anorexia (one study), Huntington’s disease (one study), insomnia (one study), and epilepsy (one study).

Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas others suggest that it may inhibit ∆9-THC-induced effects.

Finally, preliminary clinical trials suggest that high-dose oral CBD  may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation. Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed.”

Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression.

“To date, anticonvulsant effects of the plant cannabinoid, cannabidivarin (CBDV), have been reported in several animal models of seizure. However, these behaviourally observed anticonvulsant effects have not been confirmed at the molecular level…

These results provide the first molecular confirmation of behaviourally observed effects of the non-psychoactive, anticonvulsant cannabinoid, CBDV, upon chemically-induced seizures and serve to underscore its suitability for clinical development.”


Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction.

“AIMS: To review knowledge on cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction.



Components of the endocannabinoid system-cannabinoid (CB) receptor types 1 and 2, anandamide, and fatty acid amide hydrolase (FAAH), which degrades anandamide and related fatty-acid amides-have been located to lower urinary tract tissues of mice, rats, monkeys, and humans. Studies have located CB receptors in urothelium and sensory nerves and FAAH in the urothelium. CB receptor- and FAAH-related activities have also been reported in the lumbosacral spinal cord. Data on supraspinal CB functions in relation to micturition are lacking. Cannabinoids are reported to reduce sensory activity of isolated tissues, cause antihyperalgesia in animal studies of bladder inflammation, affect urodynamics parameters reflecting sensory functions in animals models, and appear to have effects on storage symptoms in humans. FAAH inhibitors have affected sensory bladder functions and reduced bladder overactivity in rat models. Cannabinoids may modify nerve-mediated functions of isolated lower urinary tract tissues.


Evidence suggests components of the endocannabinoid system are involved in regulation of bladder function, possibly at several levels of the micturition pathway. It is unclear if either CB receptor has a dominant role in modification of sensory signals or if differences exist at peripheral and central nervous sites. Amplification of endocannabinoid activity by FAAH inhibitors may be an attractive drug target in specific pathways involved in LUTS.”

Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint.

“Osteoarthritis (OA) of the joint is a prevalent disease accompanied by chronic, debilitating pain. Recent clinical evidence has demonstrated that central sensitization contributes to OA pain. An improved understanding of how OA joint pathology impacts upon the central processing of pain is crucial for the identification of novel analgesic targets/new therapeutic strategies.

Inhibitory cannabinoid 2 (CB2) receptors attenuate peripheral immune cell function and modulate central neuro-immune responses in models of neurodegeneration…

These findings suggest that targeting CB2 receptors may have therapeutic potential for treating OA pain.”

Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress.

“Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues.

Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice.

Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells.

This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells.”

“The therapy of gliomas, the most frequent class of malignant primary brain tumors and one of the most aggressive forms of cancer characterized by high invasiveness, a high proliferation rate and rich neovascularization, could benefit from the use of cannabinoids, the active compounds of Cannabis sativa, and their synthetic derivatives. They have been shown to mimic the endogenous substances named “endocannabinoids” that activate specific cannabinoid receptors (CB1 and CB2).

Cannabinoids have been proven to inhibit glioma tumor growth in either in vitro or in vivo models through several cellular pathways such as elevating ceramide levels, modulating PI3K/Akt, MAPK kinases, inducing autophagy and oxidative stress state in glioma cells, thus arresting cell proliferation and inducing apoptosis. Since cannabinoids kill tumor cells without toxicity on their non transformed counterparts, probably modulating the cell survival/cell death pathways differently, they can represent a class of new potential anticancer drugs.”

Cannabinoids (Marijuana Compounds) Lead to Leukemia Cancer Cell Destruction

marijuana anti cancer 263x166 Cannabinoids (Marijuana Compounds) Lead to Leukemia Cancer Cell Destruction

 “As new studies are released showing just how miraculous the compounds of marijuana are, the argument for legalized marijuana or at least legal access to medicinal marijuana seems to build a little more each month.

One new study, from researchers with Saint George’s University of London and published in Anticancer Research, reveals how various compounds within cannabis are able to work together to kill human leukemia cells.

The study looked at three non-psychoactive cannabinoids, including cannabidiol, cannabigerol, and cannabigevarin. These compounds were tested on two leukemia cell lines where they acted synergistically to fight the cancerous cells.

According to a press release from the University, these “non-hallucinogenic components of cannabis could act as effective anti-cancer agents.””

Read more:

The endocannabinoid system, cannabinoids, and pain.

“The endocannabinoid system is involved in a host of homeostatic and physiologic functions, including modulation of pain and inflammation… Exogenous plant-based cannabinoids (phytocannabinoids) and chemically related compounds, like the terpenes, commonly found in many foods, have been found to exert significant analgesic effects in various chronic pain conditions.

Currently, the use of Δ9-tetrahydrocannabinol is limited by its psychoactive effects and predominant delivery route (smoking), as well as regulatory or legal constraints.

 However, other phytocannabinoids in combination, especially cannabidiol and β-caryophyllene, delivered by the oral route appear to be promising candidates for the treatment of chronic pain due to their high safety and low adverse effects profiles.

This review will provide the reader with the foundational basic and clinical science linking the endocannabinoid system and the phytocannabinoids with their potentially therapeutic role in the management of chronic pain.”

Anticancer potential of Magnolia – Science

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“Anticancer potential of magnolol for lung cancer treatment… Magnolol has been reported to have anticancer property… These data indicate that magnolol is a potential candidate for treating of human lung carcinoma.”

“Magnolol induces apoptosis via caspase-independent pathways in non-small cell lung cancer cells (NSCLC). Magnolol, a hydroxylated biphenyl agent isolated from herbal planet Magnolia officinalis, is a component of traditional Asian herbal teas. It has been reported to have anti-microbial, anti-inflammatory, and anti-cancer activity… The results of this study provided a basis for understanding and developing magnolol as a novel treatment of NSCLC.”

“Magnolol-induced H460 cells death via autophagy but not apoptosis. We have reported that the protective effect of Magnolol on TBHP-induced injury in human nonsmall lung cancer H460 cells is partially via a p53 dependent mechanism… Magnolol induces H460 cells death by autophagy but not apoptotic pathway… Autophagic cells death induction by Magnolol underlines the potential utility of its induction as a new cancer treatment modality.”

“Honokiol Inhibits Non-Small Cell Lung Cancer Cell Migration by Targeting PGE2-Mediated Activation of β-Catenin Signaling… These results indicate that honokiol inhibits non-small cell lung cancer cells migration by targeting PGE2-mediated activation of β-catenin signaling… Thus intervention strategies targeting key signaling molecules of the PGE2-Wnt/β-catenin pathway may represent promising options to inhibit metastasis of lung cancer cells, and may serve as the basis for chemoprevention or therapy of lung cancer in human patients.”

“Honokiol inhibits the growth of head and neck squamous cell carcinoma by targeting epidermal growth factor receptor. Here, we report the chemotherapeutic effect of honokiol, a phytochemical fromMagnolia plant, on human head and neck squamous cell carcinoma (HNSCC). Conclusively, honokiol appears to be an attractive bioactive small molecule phytochemical for the management of head and neck cancer which can be used either alone or in combination with other available therapeutic drugs.”

“Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells. Magnolol, an active component isolated from the root and stem bark of Magnolia officinalis, has been reported to exhibit antitumour effects… Magnolol inhibited proliferation of human lung squamous carcinoma CH27 cells at low concentrations, and induced apoptosis at high concentrations…”

“Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via the mitochondrial and PI3K/Akt signaling pathways… Plants are considered as one of the most important sources for the development of anticancer drugs. Magnolol, a natural compound possesses anticancer properties…These findings provide evidence that Magnolol is a promising natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combination antitumor therapies.”

“Magnolol-Induced Apoptosis in HCT-116 Colon Cancer Cells Is Associated with the AMP-Activated Protein Kinase Signaling Pathway… Magnolol, a hydroxylated biphenyl compound present in Magnolia officinalis, exerts anticancer potential and low toxicity… These findings demonstrate that AMPK mediates the anticancer effects of magnolol through apoptosis in HCT-116 cells.”

“Honokiol in combination with radiation targets Notch signaling to inhibit colon cancer stem cells. ”

“Honokiol: a novel natural agent for cancer prevention and therapy. Honokiol is a bioactive natural product derived from Magnolia spp. Recent studies have demonstrated anti-inflammatory, anti-angiogenic, anti-oxidative and anti-cancer properties of honokiol in vitro and in preclinical models.”

“Honokiol augments the anti-cancer effects of oxaliplatin in colon cancer cells… honokiol can be used in combination with oxaliplatin in the chemotherapy of colon cancer. This combination allows a reduction in oxaliplatin dose, and thereby reduces its adverse effects. It may also enhance the chemotherapeutic effect…”

“Honokiol Eliminates Human Oral Cancer Stem-Like Cells Accompanied with Suppression of Wnt/β-Catenin Signaling and Apoptosis Induction. Honokiol, an active compound of Magnolia officinalis, exerted many anticancer effects on various types of cancer cells. We explored its effects on the elimination of cancer stem-like side population (SP) cells in human oral squamous cell carcinoma SAS cells… Our findings indicate honokiol may be able to eliminate oral cancer… ”

“Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells. We observed that treatment of prostate cancer cells for 24 h with magnolol, a phenolic component extracted from the root and stem bark of the oriental herb Magnolia officinalis, induced apoptotic cell death in a dose- and time-dependent manner… These results suggest that one of the mechanisms of the apoptotic activity of magnolol involves its effect on epidermal growth factor receptor (EGFR)-mediated signaling transduction pathways.”

“Autophagy triggered by magnolol derivative negatively regulates angiogenesis…  These studies, while disclosing the vital role of autophagy in the regulation of angiogenesis, also suggest that the potent modulators of autophagy can lead to the development of effective therapeutics in apoptosis-resistant cancer.”

“Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis. Honokiol, a small-molecule polyphenol isolated from magnolia species, is widely known for its therapeutic potential as an antiinflammatory, antithrombosis, and antioxidant agent, and more recently, for its protective function in the pathogenesis of carcinogenesis… Taken together, these data provide the first in vitro and in vivo evidence of the integral role of the LKB1-AMPK axis in honokiol-mediated inhibition of the invasion and migration of breast cancer cells. In conclusion, honokiol treatment could potentially be a rational therapeutic strategy for breast carcinoma.”

“Honokiol synergizes chemotherapy drugs in multidrug resistant breast cancer cells via enhanced apoptosis and additional programmed necrotic death… These findings indicate a promising way to circumvent MDR and apoptosis tolerance.”

“Magnolol induces apoptosis in MCF-7 human breast cancer cells through G2/M phase arrest and caspase-independent pathway. Magnolol, a small-molecule hydroxylated biphenol, isolated from the root and stem bark of Magnolia officinalis, has been shown to possess antiproliferative effect on various cancer cell lines. In the current study, we found that magnolol potently inhibited proliferation and induced apoptosis in MCF-7 human breast cancer cells…  Our findings indicated that magnolol induced apoptosis in MCF-7 cells via the intrinsic pathway with release of AIF from mitochondrial and G2/M phase arrest pathway. Therefore, magnolol might be a potential lead compound in the therapy of breast cancer.”

“Screening active anti-breast cancer compounds from Cortex Magnolia officinalis by 2D LC-MS.”

“Magnolol Suppresses Vascular Endothelial Growth Factor-Induced Angiogenesis by Inhibiting Ras-Dependent Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt Signaling Pathways. Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been reported to possess anticancer activity. Recent studies have also demonstrated that magnolol inhibits cell growth and induces the apoptosis of cancer cells… these results demonstrate that magnolol is an inhibitor of angiogenesis and suggest that this compound could be a potential candidate in the treatment of angiogenesis-related diseases.”

“Magnolol suppresses hypoxia-induced angiogenesis via inhibition of HIF-1α/VEGF signaling pathway in human bladder cancer cells… Magnolol isolated from Magnolia officinalis has been reported to exhibit an anticancer activity via elevation of apoptosis… these findings strongly indicate that the anti-agngiogenic activity of magnolol is, at least in part, mediated by suppressing HIF-1α/VEGF-dependent pathways, and suggest that magnolol may be a potential drug for human bladder cancer therapy.”

“Signaling pathway for TNF-alpha-induced MMP-9 expression: mediation through p38 MAP kinase, and inhibition by anti-cancer molecule magnolol in human urinary bladder cancer 5637 cells.”

“Wnt/β-Catenin Signaling Mediates the Antitumor Activity of Magnolol in Colorectal Cancer Cells… In summary, the present study demonstrates that magnolol might be a potential candidate in the development of small molecule inhibitors of Wnt signaling. Therefore, magnolol might be useful for treating sporadic colon cancer cells either alone or in combination with other chemotherapeutic agents.”

“Targeting apoptosis pathways in cancer with magnolol and honokiol, bioactive constituents of the bark of Magnolia officinalis… Magnolol and honokiol were found to possess anti-tumor activity by targeting the apoptosis pathways, which have been considered as targets for cancer therapies…These breakthrough findings may have important implications for targeted cancer therapy and modern applications of traditional Chinese medicine.”

“Design and synthesis of novel magnolol derivatives as potential antimicrobial and antiproliferative compounds.”

“Effects of magnolol on UVB-induced skin cancer development in mice and its possible mechanism of action. Magnolol, a plant lignan isolated from the bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on chemically-induced skin cancer development… Magnolol pretreatments prevent UVB-induced skin cancer development by enhancing apoptosis, causing cell cycle arrest at G2/M phase, and affecting various signaling pathways. Magnolol could be a potentially safe and potent anticarcinogenic agent against skin cancer.”

“Time and dose-response effects of honokiol on UVB-induced skin cancer development…Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer… . Honokiol prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.”

“Honokiol, a chemopreventive agent against skin cancer, induces cell cycle arrest and apoptosis in human epidermoid A431 cells. Honokiol is a plant lignan isolated from bark and seed cones of Magnolia officinalis. Recent studies from our laboratory indicated that honokiol pretreatment decreased ultraviolet B-induced skin cancer development in SKH-1 mice…These findings indicate that honokiol provides its effects in squamous carcinoma cells by inducing cell cycle arrest at G0/G1 phase and apoptosis.”

“Honokiol potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through modulation of nuclear factor-kappaB activation pathway… Recent reports have indicated that honokiol can induce apoptosis, suppress tumor growth, and inhibit angiogenesis.”

“Magnolol induces apoptosis via activation of both mitochondrial and death receptor pathways in A375-S2 cells. Magnolol inhibited proliferation of human malignant melanoma A375-S2 cells…  our results indicate that magnolol induces apoptosis by activation of both mitochondrial and death receptor pathways in A375-S2 cells.”

“Honokiol induces cytotoxic and cytostatic effects in malignant melanoma cancer cells… Honokiol is highly effective in inhibiting melanoma cancer cells by attenuating AKT/mammalian target of rapamycin and Notch signaling. These studies warrant further clinical evaluation for honokiol alone or with present chemotherapeutic regimens for the treatment of melanomas.”

“Studies on inhibitors of skin tumor promotion, IX. Neolignans from Magnolia officinalis… This investigation indicates that these neolignans and the extract might be valuable antitumor promoters.”

“Inhibitory effect of magnolol on TPA-induced skin inflammation and tumor promotion in mice. Magnolol has been reported to have an anti-inflammatory and antitumor effect in vitro and in vivo…  All these results revealed that magnolol is an effective antitumor agent…”

“Magnolol down-regulates HER2 gene expression, leading to inhibition of HER2-mediated metastatic potential in ovarian cancer cells… Magnolol has been reported to exhibit anti-tumor activities…  These results provide a novel mechanism to explain the anti-cancer effect of magnolol.”

“Magnolol Suppresses Metastasis via Inhibition of Invasion, Migration, and Matrix Metalloproteinase-2/-9 Activities in PC-3 Human Prostate Carcinoma Cells. Magnolol, a hydroxylated biphenyl compound isolated from the root and stem bark of Magnolia officinalis, has been reported to have anticancer activity… These results demonstrate the antimetastatic properties of magnolol in inhibiting the adhesion, invasion, and migration of PC-3 human prostate cancer cells.”

“Magnolol inhibits human glioblastoma cell proliferation through upregulation of p21/Cip1. Previously, we demonstrated that magnolol isolated from the bark of Magnolia officinalis has anticancer activity in colon, hepatoma, and leukemia cell lines. In this study, we show that magnolol concentration dependently decreased the cell number in a cultured human glioblastoma cancer cell line…  Our findings suggest the potential applications of magnolol in the treatment of human brain cancers.”

“Mechanisms for the magnolol-induced cell death of CGTH W-2 thyroid carcinoma cells. Magnolol, a substance purified from the bark of Magnolia officialis, inhibits cell proliferation and induces apoptosis in a variety of cancer cells. The aim of this study was to study the effects of magnolol on CGTH W-2 thyroid carcinoma cells…  These results show that magnolol initiates apoptosis via the cytochrome-c/caspase 3/PARP/AIF and PTEN/Akt/caspase 9/PARP pathways and necrosis via PARP activation.”

“In vitro anti-mutagenic effect of magnolol against direct and indirect mutagens. Magnolol, a component of the bark of Magnolia obovata, has been reported to possess various biological activities, such as anti-carcinogenicity, anti-promotion activity and anti-oxidative activity. These findings suggest potential for this compound in cancer chemoprevention.”

“Molecular mechanisms of apoptosis induced by magnolol in colon and liver cancer cells. Magnolol has been reported to have anticancer activity.”

“Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA synthesis and activating apoptosis. Magnolol, a hydroxylated biphenyl compound isolated from the Chinese herb Hou p’u of Magnolia officinalis, has been reported to have anti-cancer activity…  These findings demonstrate for the first time that magnolol can inhibit the proliferation of tumor cells in vitro and in vivo.”

“Inhibitory effect of magnolol on tumour metastasis in mice. It has previously been reported that magnolol, a phenolic compound isolated from Magnolia obovata, inhibited tumour cell invasion in vitro. The purpose of this study was to investigate the antimetastatic effect of magnolol on tumour metastasis in vivo… These data from the in vivo experiments suggest that magnolol possesses strong antimetastatic ability and that it may be a lead compound for drug development. The antimetastatic action of magnolol is considered to be due to its ability to inhibit tumour cell invasion.”

“Therapeutic applications of compounds in the Magnolia family… anti-cancer, anti-stress, anti-anxiety, anti-depressant, anti-oxidant, anti-inflammatory and hepatoprotective…”

“Magnolia Extract Fights Difficult-to-Treat Cancers”

“Magnolia dealbata seeds extract exert cytotoxic and chemopreventive effects on MDA-MB231 breast cancer cells. Magnolia dealbata Zucc (Magnoliaceae), a Mexican endemic species, is used for the empirical treatment of cancer. Objective: To evaluate the cytotoxic and cancer chemopreventive effects of an ethanol extract of Magnolia dealbata seeds (MDE)… Conclusions: MDE exerts cytotoxic, apoptotic and chemopreventive activities on MDA-MB231 human cancer cells.”

Cannabidiol, a Non-Psychoactive Cannabinoid Compound, Inhibits Proliferation and Invasion in U87-MG and T98G Glioma Cells through a Multitarget Effect.

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“…the non-psychoactive cannabinoid compound cannabidiol (CBD) effectively limits human glioma cell growth, both in vitro and in vivo… the present investigation confirms the antiproliferative and antiinvasive effects of CBD in U87-MG cells.

 More interestingly, these effects can also be extended to T98G glioma cells, a well known Δ9-THC-resistant lineage…

Taken together, these results provide new insights into the antitumor action of CBD, showing that this cannabinoid affects multiple tumoral features and molecular pathways.

 As CBD is a non-psychoactive phytocannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anti-cancer drug in the management of gliomas.”


Anti-cancer effects of D-limonene – Science


“Chemoprevention and therapy of cancer by d-limonene. The naturally occurring monoterpene d-limonene has chemopreventive and chemotherapeutic activity… The complete regression of mammary carcinomas by limonene… The multiple antitumorigenic effects of limonene are attainable at a high therapeutic ratio, suggesting that limonene and related monoterpenes may be efficacious in the chemoprevention and chemotherapy of human malignancies.”

“D-Limonene: safety and clinical applications. D-limonene is one of the most common terpenes in nature…  D-limonene is listed in the Code of Federal Regulations as generally recognized as safe… D-limonene has well-established chemopreventive activity against many types of cancer.”

“Cancer Chemoprevention by Phytochemicals and their Related Compounds. Cancer chemoprevention by phytochemicals may be one of the most feasible approaches for cancer control… phytochemicals obtained from vegetables, fruits, spices, teas, herbs and medicinal plants… have been proven to suppress experimental carcinogenesis in various organs.”

“d-limonene, an anticarcinogenic terpene.”

“Limonene exerts antiproliferative effects and increases nitric oxide levels on a lymphoma cell line by dual mechanism of the ERK pathway: relationship with oxidative stress. D-limonene is a common monoterpene found in nature. Previously, it has been demonstrated that it has antiproliferative effects on a lymphoma cell line…

“Effect of D-limonene on immune response in BALB/c mice with lymphoma. The monoterpene D-limonene and its metabolites have been shown to exert chemopreventive and chemotherapeutic activities against different tumors in animal models and clinical trials… Our data suggest that in addition to reported properties, D-limonene modulates the immune response with significant potential for clinical application.”

“Limonene-induced regression of mammary carcinomas. Dietary administration of the monocyclic monoterpenoid d-limonene causes complete regression of both dimethylbenz[alpha]anthracene- and N-nitroso-N-methylurea-induced rat mammary carcinomas. Carcinomas regress when limonene is added to the diet… Its removal from the diet results in a significant number of tumor recurrences…  Monoterpenoids such as limonene represent a novel class of anticancer drugs with the potential to cause tumor regressions with limited toxicity.”

“d-Limonene inhibits N-nitrosobis(2-oxopropyl)amine induced hamster pancreatic carcinogenesis… quantitative histological analysis showed that prolonged treatment with d-limonene significantly reduced the number of pancreatic carcinomas…These findings indicate that d-limonene inhibits the development of pancreatic carcinoma…”

“Inhibition by D-limonene of gastric carcinogenesis induced by N-methyl-N’-nitro-N-nitrosoguanidine in Wistar rats… These findings indicate that limonene inhibits the development of gastric cancers through increased apoptosis and decreased DNA synthesis of gastric cancers…”

“Inhibition by d-limonene of experimental hepatocarcinogenesis in Sprague-Dawley rats does not involve p21(ras) plasma membrane association… These findings indicate that limonene inhibits hepatocarcinogenesis and suggest that this effect may be clearly related to its effect in inhibiting cell proliferation and in enhancing apoptosis…”

“Inhibition of growth and metastasis of human gastric cancer implanted in nude mice by d-limonene… d-limonene has antiangiogenic and proapoptotic effects on gastric cancer, thereby inhibits tumor growth and metastasis.”

“D-limonene induces apoptosis of gastric cancer cells.”

“Apoptosis: programmed cell death at a molecular level.”

“d -Limonene sensitizes docetaxel-induced cytotoxicity in human prostate cancer cells: Generation of reactive oxygen species and induction of apoptosis…  Our results show, for the first time, that d -limonene enhanced the antitumor effect of docetaxel against prostate cancer cells without being toxic to normal prostate epithelial cells. The combined beneficial effect could be through the modulation of proteins involved in mitochondrial pathway of apoptosis. d -Limonene could be used as a potent non-toxic agent to improve the treatment outcome of hormone-refractory prostate cancer with docetaxel.”

“Induction of apoptosis by D-limonene is mediated by inactivation of Akt in LS174T human colon cancer cells. D-limonene is recognized as a potential chemotherapeutic agent… d-limonene induced apoptosis via the mitochondrial death pathway and the suppression of the PI3K/Akt pathway.”

“Induction of apoptosis by d-limonene is mediated by a caspase-dependent mitochondrial death pathway in human leukemia cells… anti-tumoral activity of d-limonene, a monocyclic monoterpene, in human leukemia cells… Our findings and data, all suggest that the mitochondrial death pathway is primarily involved in the development of d-limonene-induced apoptosis.”

“Effects of D-limonene on leukemia cells HL-60 and K562 in vitro… It is concluded that D-L can inhibit proliferation and induce apoptosis of HL-60 and K562 cells…”

“Proliferation inhibition and apoptosis induction of K562 cells by D-limonene… It is concluded that the D-limonene can inhibit proliferation of K562 cells in dose-dependent manner, cause cell detained at G1 phase and induce apoptosis of K562 cells.”

“Inhibition of tumor progression by naturally occurring terpenoids.”

“Effect of naturally occurring monoterpenes carvone, limonene and perillic acid in the inhibition of experimental lung metastasis induced by B16F-10 melanoma cells… These results indicate that limonene and perillic acid could inhibit the metastatic progression of B16F-10 melanoma cells…”

“Antitumorigenic effects of limonene and perillyl alcohol against pancreatic and breast cancer… Perillyl alcohol and d-limonene, a closely related dietary monoterpene, have chemotherapeutic activity against pancreatic, mammary, and prostatic tumors. In addition, perillyl alcohol, limonene, and other dietary monoterpenes have chemopreventive activity… Monoterpenes are effective, nontoxic dietary antitumor agents which act through a variety of mechanisms of action and hold promise as a novel class of antitumor drugs for human cancer.”

“Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee. D-Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer…D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.”

“Human metabolism of the experimental cancer therapeutic agent d-limonene. d-Limonene has efficacy in preclinical models of breast cancer, causing > 80% of carcinomas to regress with little host toxicity… Limonene is metabolized by humans and rats in a similar manner. These observations and the high therapeutic ratio of limonene in the chemotherapy of rodent cancers suggest that limonene may be an efficacious chemotherapeutic agent for human malignancies.”

“Inhibition of DMBA-induced mammary cancer by the monoterpene d-limonene… In addition to inhibiting the appearance of mammary tumors, d-limonene was also found to cause the regression of frank mammary tumors. No toxicity was evident in these rats even at the highest d-limonene dose…”

“D-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis. D-Limonene, a common monoterepene has been shown to have antiproliferative, apoptosis-inducing and chemopreventive effects…”

“Cancer Prevention by Natural Compounds.”

“Molecular targets of dietary agents for prevention and therapy of cancer… fruits and vegetables are recommended for prevention of cancer and other diseases… The active principle identified in fruit and vegetables and the molecular targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food.”

“”D-Limonene is one of the most important terpenes found in cannabis/hemp. It has shown significant anti-cancer properties in a number of studies.”… D-Limonene is thought to be responsible for much of the relaxing effects of smoked cannabis. These effects are often absent in refined cannabinoid extracts which have many of the elements of the plant removed…”While the cannabinoids are only to be found in marijuana / hemp, many of the terpenes are found in a wide variety of different plants. The D-limonene in Dharmanol ™ is identical to that in all varieties of cannabis, but is sourced from other plants.”