Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation

Zgair, Atheer; Lee, Jong Bong; Wong, Jonathan; Taha, Dhiaa A.; Aram, Jehan; Virgilio, D. Di; McArthur, Joshua W.; Cheng, Yu-Kit; Hennig, I.; Barrett, David A.; Fischer, Peter M.; Constantinescu, Cris S.; Gershkovich, Pavel

doi:10.1038/s41598-017-15026-z

Cited by 107 publications

(114 citation statements)

References 56 publications

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“…Indeed, CBD (1-20 lg/mL or 3.2-64 lM) suppressed IL-17A production in human CD3 + T cells (derived from healthy patients or patients with MS or nonseminomatous germ cell tumors) stimulated ex vivo with PMA/Io. 146 Taken together with the data described in innate cells above, it is clear that CBD's action in inflammation and immune function involves suppression of cytokine production from many different cell types.…”

Section: Cbd Effects and Mechanisms Of Immune Suppression In Lymphocytesmentioning

confidence: 82%

Immune Responses Regulated by Cannabidiol

Nichols

Kaplan

2020

Cannabis and Cannabinoid Research

209

176

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Introduction: Cannabidiol (CBD) as Epidiolex Ò (GW Pharmaceuticals) was recently approved by the U.S. Food and Drug Administration (FDA) to treat rare forms of epilepsy in patients 2 years of age and older. Together with the increased societal acceptance of recreational cannabis and CBD oil for putative medical use in many states, the exposure to CBD is increasing, even though all of its biological effects are not understood. Once such example is the ability of CBD to be anti-inflammatory and immune suppressive, so the purpose of this review is to summarize effects and mechanisms of CBD in the immune system. It includes a consideration of reports identifying receptors through which CBD acts, since the ' 'CBD receptor,' ' if a single one exists, has not been definitively identified for the myriad immune system effects. The review then provides a summary of in vivo and in vitro effects in the immune system, in autoimmune models, with a focus on experimental autoimmune encephalomyelitis, and ends with identification of knowledge gaps. Conclusion: Overall, the data overwhelmingly support the notion that CBD is immune suppressive and that the mechanisms involve direct suppression of activation of various immune cell types, induction of apoptosis, and promotion of regulatory cells, which, in turn, control other immune cell targets.

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Section: Cbd Effects and Mechanisms Of Immune Suppression In Lymphocytesmentioning

confidence: 82%

Immune Responses Regulated by Cannabidiol

Nichols

Kaplan

2020

Cannabis and Cannabinoid Research

209

176

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“…In addition, the intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, metastasis of some solid tumours, and human immunodeficiency virus (HIV) infection. Therefore, efficient delivery of drugs to the intestinal lymphatic system has potential to improve treatment of diseases such as autoimmune disorders, lymphatic system-associated cancers, HIV infections and cancer metastasis [ [3] , [4] , [5] , [6] ]. However, only a very limited proportion of a drug can usually be distributed from the systemic circulation into the lymphatic system [ 4 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system

Lee

Zgair

Malec

et al. 2018

Journal of Controlled Release

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The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions.

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“…The immune-regulatory properties of cannabis and cannabinoid-based treatments were demonstrated in various preclinical and clinical studies. [15][16][17] It is therefore important to investigate the effects of cannabinoid-based treatments on the immunity of cancer patients and on the efficacy of immunerelated therapies. With a greater understanding of cannabinoid-based treatment effects on the immune system we will be able to appropriately apply them to treatment of cancer patients in combination with existing therapies.…”

Section: Cannabis and Immunity In Cancer Patientsmentioning

confidence: 99%

“…20 In an ex vivo experiment, Zgair et al showed that both phytocannabinoids cannabidiol (CBD) and THC have anti-proliferative effects on peripheral blood mononuclear cells (PBMC) isolated from patients on chemotherapy regimens to treat non-seminomatous germ cell tumors, which were comparable to the effect on PBMCs from healthy volunteers. 16 Only one study has investigated the interaction between phyto-cannabinoids and immunotherapy with checkpoint inhibitors. In this retrospective, observational study in kidney cancer and melanoma patients, Taha et al demonstrated an inverse relationship between cannabis use and the response to treatment with nivolumab, without affecting progression-free survival or overall survival and without relation to specific phyto-cannabinoid composition.…”

Section: Cannabis and Immunity In Cancer Patientsmentioning

confidence: 99%

The Highs and Lows of Cannabis in Cancer Treatment and Bone Marrow Transplantation

Almogi-Hazan

Khuja

Ritter³

et al. 2020

Rambam Maimonides Med J

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In the last decade, we have observed an increased public and scientific interest in the clinical applications of medical cannabis. Currently, the application of cannabinoids in cancer patients is mainly due to their analgesic and anti-emetic effects. The direct effects of phyto-cannabinoids on cancer cells are under intensive research, and the data remain somewhat inconsistent. Although anti-proliferative properties were observed in vitro, conclusive data from animal models and clinical trials are lacking. Since immunotherapy of malignant diseases and bone marrow transplantation are integral approaches in hemato-oncology, the immuno-modulatory characteristic of cannabinoids is a fundamental aspect for consideration. The effect of cannabinoids on the immune system is presently under investigation, and some evidence for its immunoregulatory properties has been shown. In addition, the interaction of cannabinoids and classical cytotoxic agents is a subject for further investigation. Here we discuss the current knowledge of cannabinoid-based treatments in preclinical models and the limited data in oncological patients. Particularly, we address the possible contradiction between the direct anti-tumor and the immune-modulatory effects of cannabinoids.

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Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation

Cited by 107 publications

References 56 publications

Immune Responses Regulated by Cannabidiol

Immune Responses Regulated by Cannabidiol

Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system

The Highs and Lows of Cannabis in Cancer Treatment and Bone Marrow Transplantation

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