Special considerations
Anti-inflammatory effects with cannabinoids and potential interfer- ence with immunosuppressive medications, immunotherapy and other chemotherapies Effects of cannabinoids on standard chemotherapy and immunotherapies are largely unknown. Chemotherapy agents metabolized by the liver may share similar metabolic pathways to cannabinoids and pharmacodynamic interactions cannot be excluded. Interestingly, a retrospective study suggested concurrent treatment with medical cannabis and the immunotherapy drug nivolumab in non-gynecologic malignancies was associated with a reduced overall response rate. An open discussion with patients regarding the possible risks and benefits of treatment with cannabis is strongly encouraged. In addition to direct effects on neuropathic pain and cancer-related pain, cannabinoids possess anti-inflammatory properties. Endocannabinoid system receptors, CB1 and CB2, both play a role in immune function. The highest levels of CB2 are expressed in B lymphocytes, but other immune cells, including macrophages, monocytes, NK cells, and polymorphonuclear cells, express CB2. The immunomodulatory effects of THC and other cannabinoids are primarily through the CB2 receptor. Immunomodulation is accomplished through induction of apoptosis, suppression of cell proliferation, inhibition of pro-inflammatory cytokines and chemokine production, increase in anti-inflammatory cytokines, and induction of regulator T-cells. CBD has been further studied for its anti-inflammatory or immunomodulating effects, as its limited psychoactive side effects allow for expanded use. CBD has shown inverse agonistic effects on tissues with CB2 receptors, which can block migration of immune cells and thus decrease inflammation. CBD has also exhibited agonistic effects at the CB2 receptor. Clinically, CBD demonstrates immunosuppressive effects through the CB2 receptor and other pathways. Various studies have demonstrated immunosuppression to noxious stimuli, reducing pro-inflammatory cytokines such as TNF-alpha, interleukin-6, interleukin-1Beta, and IFN-beta, with potential benefit for chronic inflammatory disease such as Crohn's Disease. Remarkably, CBD has also stimulated NK T cell production and increased production of IL-12, thus acting as an immune stimulator. This effect may account for the proposed anti-tumor properties of CBD. Despite the therapeutic effects of CBD for inflammatory conditions, the complex interplay of CBD and other cannabinoids with the immune system raises many questions within the changing environment of oncology care. Immunotherapies, including PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, and CAR-T cells, have recently been approved or are currently being tested in clinical trials for gynecologic cancers. These therapies allow for T cell activation for the elimination of cancer cells. The potential exists for muted response or enhanced toxicity of immunotherapy by cannabinoids. Additional studies of cannabinoid use with immunotherapy are urgently needed. Cannabinoids may also dampen the ability to respond to infections encountered during cancer treatment. However, controversy surrounds this concept, as cannabinoids have also demonstrated antibacterial properties in vitro and may control a damaging sepsis response. Antitumor properties of cannabis In addition to symptom relief, much attention has been focused on the direct antitumor properties of cannabis. In vitro studies, as well as in vivo studies, in rodent models have demonstrated antiproliferative activity in tumor cell cultures and xenografts with exposure to cannabinoids. Direct and indirect mechanisms of action for these observed antitumor properties have been reported, included halting of angiogenesis and impaired metastasis.. The concept of combination anticancer therapy has recently been applied to cannabinoids. Recent studies have reported combined THC and temozolomide administration in glioma xenografts had a profound antitumor action. Combination THC and CBD has also been studied with promising activity in in vitro studies. Clinical trials in humans are in their infancy, but early studies have demonstrated safety and reduction in tumor progression. The majority of evidence for the antitumoral effect of cannabinoids is in pre-clinical studies, and caution should be exercised when discussing these effects with patients. Interactions with current treatment strategies and potential for improved efficacy should be explored with phase I and II trials. Risks of using medical cannabis in high risk populations Special consideration should be given to “at risk” populations when discussing the risks and benefits of cannabinoids. Use in adolescent patients carries an increased risk of mental illness (anxiety, depression, schizophrenia) and an increased risk of addiction to other substances. There are additional cognitive and brain development risks that are incompletely understood. The risk of female infertility is increased due to the central effects on the hormonal axis resulting in oligo-ovulation. Elderly patients should be counseled about side effects including cardiovascular risk, abnormal cognition, and falls risk. In patients diagnosed with mental health conditions great caution should be exercised, especially with THC-containing products. Although some research has demonstrated improvements in certain behavioral conditions, such as anxiety and PTSD, there is evidence that there is increased risk of manic episodes in bipolar illness, panic attacks and increased anxiety, and hallucinations or psychosis. Providers are directed to carefully review the updated literature as more information is published regarding adverse effects of cannabinoids, especially in higher risk populations. (III)
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