Care After Chemotherapy: Peripheral Neuropathy, Cannabis for Symptom Control, and Mindfulness.

ASCO Educational Book

“As cancer therapies improve, patients are living longer. With these improvements in therapy comes a responsibility to optimize patients’ quality of life during cancer therapy and beyond. This report reviews three timely and important topics.

The first section reviews the mechanism underlying chemotherapy-induced peripheral neuropathy and evaluates the evidence for interventions to prevent and treat peripheral neuropathy. It also provides a framework for approaching the diagnosis and management of this common and bothersome side effect.

The second section addresses the controversial but effective use of cannabinoids for cancer and chemotherapy symptoms. Although clinical trials are difficult to conduct because of the political and social stigma of this class of drugs, this review provides evidence of the efficacy of cannabinoids for treatment of pain and nausea.

The last section addresses the mind-body connection, with a focus on the negative emotions patients with cancer often experience. This section assesses the literature regarding mindfulness-based programs to improve cancer-related stress. These three topics may appear unrelated, but all address one common goal: treating the body and the mind to optimize quality of life during and after cancer therapy.”

“Although commercially available dronabinol is not superior to other antiemetics and oromucosal nabiximols is not very effective for treating cancer pain, cannabis has been shown to be effective for treating pain and may help patients reduce opioid intake.”
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Oral cannabinoid-rich THC/CBD cannabis extract for secondary prevention of chemotherapy-induced nausea and vomiting: a study protocol for a pilot and definitive randomised double-blind placebo-controlled trial (CannabisCINV).

BMJ Journals

“Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV.

METHODS AND ANALYSIS:

The current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5 mg) capsules or placebo capsules three times a day on day -1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day -1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients.

ETHICS AND DISSEMINATION:

The protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.”

https://www.ncbi.nlm.nih.gov/pubmed/30209152

https://bmjopen.bmj.com/content/8/9/e020745

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Cannabis for the Management of Cancer Symptoms: THC Version 2.0?

Cannabis and Cannabinoid Research cover image

“The landscape of medical cannabis is rapidly expanding. Cannabis preparations have been used in medicine for millennia, and now there is a strong renaissance in the study of their therapeutic properties.

The vast majority of controlled clinical trials that support the medical use of what is commonly known as “cannabis” or “marijuana” have actually been conducted with purified cannabinoids or a single extract of Cannabis sativa that contains an equimolecular proportion of Δ9-THC and CBD.

Based on these studies, THC/dronabinol (Marinol) and its synthetic analogue nabilone (Cesamet), as well as nabiximols (Sativex), are already approved by several regulatory agencies, including FDA, Health Canada, and EMA, as antiemetic, anticachexic, analgesic, or antispastic medicines.

This study provides a precious piece of information on the use of medical cannabis for the management of cancer symptoms.”

https://www.liebertpub.com/doi/10.1089/can.2018.0009

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The use of cannabis in supportive care and treatment of brain tumor

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“Anticancer Effects of Cannabinoids may be able to Prolong Life.

Cannabinoids are multitarget substances. Currently available are dronabinol (synthetic delta-9-tetrahydrocannabinol, THC), synthetic cannabidiol (CBD) the respective substances isolated and purified from cannabis, a refined extract, nabiximols (THC:CBD = 1.08:1.00); and nabilone, which is also synthetic and has properties that are very similar to those of THC.

Cannabinoids have a role in the treatment of cancer as palliative interventions against nausea, vomiting, pain, anxiety, and sleep disturbances. THC and nabilone are also used for anorexia and weight loss, whereas CBD has no orexigenic effect. The psychotropic effects of THC and nabilone, although often undesirable, can improve mood when administered in low doses. CBD has no psychotropic effects; it is anxiolytic and antidepressive.

Of particular interest are glioma studies in animals where relatively high doses of CBD and THC demonstrated significant regression of tumor volumes (approximately 50% to 95% and even complete eradication in rare cases). Concomitant treatment with X-rays or temozolomide enhanced activity further. Similarly, a combination of THC with CBD showed synergistic effects. Although many questions, such as on optimized treatment schedules, are still unresolved, today’s scientific results suggest that cannabinoids could play an important role in palliative care of brain tumor patients.

THC, a partial CB1, CB2 agonist, has the stigma of psychotropic effects that are mediated by CB1 stimulation. However, CB1 stimulation is necessary for improving mood and appetite and many other effects. At present, it is hard to imagine a better approach than adjusting THC doses individually to balance wanted versus unwanted effects. Generally, higher doses are needed to achieve analgesic and antiemetic effects. Even much higher, supraphysiologic oral doses would be needed to combat tumors.

Combinations were synergistic under many circumstances such as in pain and antitumor studies. Cannabinoids differ in their antitumor activities and probably in their mechanisms and targets, which is a rationale for combinations. However, for many pharmacological effects (except against tumors) roughly 10-times higher daily doses are needed for CBD compared to THC.

In summary, the endocannabinoid system is likely playing a crucial role in palliative care. The future will show whether an optimized treatment strategy with cannabinoids can also prolong life of brain tumor patients by their virtue to combat cancer cells.”

https://academic.oup.com/nop/article/4/3/151/2918616

“Cannabinoid Drug Prolongs the Life of Brain Tumor Patients in Phase II Trials”  https://labiotech.eu/gw-pharmaceuticals-brain-tumor/

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Cannabidiol to Improve Mobility in People with Multiple Sclerosis

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“Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that affects an estimated 2.3 million people worldwide. The symptoms of MS are highly varied but frequently include pain, muscle spasticity, fatigue, inflammation, and depression. These symptoms often lead to reduced physical activity, negatively impact functional mobility, and have a detrimental impact on patients’ quality of life.

Although recent years have seen significant advances in disease modifying therapy, none of the current treatments halts or cures MS related symptoms. As a consequence, many people with MS (PwMS) look for alternative and complementary therapies such as cannabis.

The cannabis plant contains many biologically active chemicals, including ~60 cannabinoids. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are typically the most concentrated chemical components of cannabis and believed to primarily drive therapeutic benefit.

There is evidence that CBD has a number of beneficial pharmacological effects. It is anti-inflammatory, antioxidative, antiemetic, antipsychotic, and neuroprotective. The review of 132 original studies by Bergamaschi et al. describes the safety profile of CBD by highlighting that catalepsy is not induced and physiological parameters (heart rate, blood pressure, and body temperature) are not altered. Moreover, psychomotor and psychological functions are not negatively affected. High doses of up to 1,500 mg per day and chronic use have been repeatedly shown to be well tolerated by humans.

Additionally, there is also evidence that CBD may reduce the negative psychotropic effects, memory impairment, and appetite stimulation, anxiety and psychotic-like states of THC while enhancing its positive therapeutic actions.

 Anecdotal reports indicate that an increasing number of PwMS use cannabis (medical marijuana) as a supplement to improve their mobility.

Based on the following considerations, it is our opinion that CBD supplementation maybe advisable for PwMS to reduce fatigue, pain, spasticity, and ultimately improve mobility. “

https://www.frontiersin.org/articles/10.3389/fneur.2018.00183/full

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Suppression of Cisplatin-Induced Vomiting by Cannabis sativa in Pigeons: Neurochemical Evidences.

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“Cannabis sativa (CS, family Cannabinaceae) has been reported for its anti-emetic activity against cancer chemotherapy-induced emesis in animal models and in clinics. The current study was designed to investigate CS for potential effectiveness to attenuate cisplatin-induced vomiting in healthy pigeons and to study the impact on neurotransmitters involved centrally and peripherally in the act of vomiting.

High-performance liquid chromatography system coupled with electrochemical detector was used for the quantification of neurotransmitters 5-hydroxytryptamine (5HT), dopamine (DA) and their metabolites; Di-hydroxy Phenyl Acetic acid (Dopac), Homovanillic acid (HVA), and 5-hydroxy indole acetic acid (5HIAA) centrally in specific brain areas (area postrema and brain stem) while, peripherally in small intestine. Cisplatin (7 mg/kg i.v.) induce emesis without lethality across the 24 h observation period.

CS hexane fraction (CS-HexFr; 10 mg/kg) attenuated cisplatin-induced emesis ∼ 65.85% (P < 0.05); the reference anti-emetic drug, metoclopramide (MCP; 30 mg/kg), produced ∼43.90% reduction (P < 0.05). At acute time point (3rd h), CS-HexFr decreased (P < 0.001) the concentration of 5HT and 5HIAA in the area postrema, brain stem and intestine, while at 18th h (delayed time point) CS-HexFr attenuated (P < 0.001) the upsurge of 5HT caused by cisplatin in the brain stem and intestine and dopamine in the area postrema. CS-HexFr treatment alone did not alter the basal neurotransmitters and their metabolites in the brain areas and intestine except 5HIAA and HVA, which were decreased significantly.

In conclusion the anti-emetic effect of CS-HexFr is mediated by anti-serotonergic and anti-dopaminergic components in a blended manner at the two different time points, i.e., 3rd and 18th h in pigeons.”

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The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial.

Supportive Care in Cancer

“Over one half of the patients diagnosed with advanced lung cancer experience anorexia. In addition to its high incidence, cancer-induced anorexia promotes the development of the anorexia-cachexia syndrome, which is related to poor clinical outcomes.

Recently, drugs derived from cannabinoids, such as Nabilone, have been recognized for their appetite improvement properties.

METHODS:

This is a randomized, double-blind, placebo-controlled clinical trial to assess the effect of Nabilone vs. placebo on the appetite, nutritional status, and quality of life in patients diagnosed with advanced Non-small cell lung cancer (NSCLC) (NCT02802540).

CONCLUSION:

Nabilone is an adequate and safe therapeutic option to aid in the treatment of patients diagnosed with anorexia. Larger trials are necessary in order to draw robust conclusions in regard to its efficacy in lung cancer patients.”

https://www.ncbi.nlm.nih.gov/pubmed/29550881

“Nabilone is a synthetic cannabinoid with therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic pain. It mimics tetrahydrocannabinol (THC), the primary psychoactive compound found naturally occurring in Cannabis.”  https://en.wikipedia.org/wiki/Nabilone
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The current state and future perspectives of cannabinoids in cancer biology.

Cancer Medicine

“To date, cannabinoids have been allowed in the palliative medicine due to their analgesic and antiemetic effects, but increasing number of preclinical studies indicates their anticancer properties. Cannabinoids exhibit their action by a modulation of the signaling pathways crucial in the control of cell proliferation and survival. Many in vitro and in vivo experiments have shown that cannabinoids inhibit proliferation of cancer cells, stimulate autophagy and apoptosis, and have also a potential to inhibit angiogenesis and metastasis. In this review, we present an actual state of knowledge regarding molecular mechanisms of cannabinoids’ anticancer action, but we discuss also aspects that are still not fully understood such as the role of the endocannabinoid system in a carcinogenesis, the impact of cannabinoids on the immune system in the context of cancer development, or the cases of a stimulation of cancer cells’ proliferation by cannabinoids. The review includes also a summary of currently ongoing clinical trials evaluating the safety and efficacy of cannabinoids as anticancer agents.”

https://www.ncbi.nlm.nih.gov/pubmed/29473338

http://onlinelibrary.wiley.com/doi/10.1002/cam4.1312/abstract

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Cannabinoids for nausea and vomiting related to chemotherapy: Overview of systematic reviews.

Phytotherapy Research

“Nausea and vomiting are common and distressing adverse events of chemotherapy.

This review focuses on the findings and quality of systematic reviews (SRs) of cannabinoids for chemotherapy-induced nausea and vomiting (CINV).

On the basis of findings of the sole SR judged as high methodological quality, cannabinoids seem to be more effective than placebo, equal to prochlorperazine for reducing CINV, and to be preferred by patients.

Cannabinoids represent a valuable option for treating CINV, despite the adverse events related to treatment, such as drowsiness and cognitive impairment.”   https://www.ncbi.nlm.nih.gov/pubmed/29168289

http://onlinelibrary.wiley.com/doi/10.1002/ptr.5975/abstract?systemMessage=Wiley+Online+Library+usage+report+download+page+will+be+unavailable+on+Friday+24th+November+2017+at+21%3A00+EST+%2F+02.00+GMT+%2F+10%3A00+SGT+%28Saturday+25th+Nov+for+SGT+

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Cannabinoid signaling in health and disease.

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“Cannabis sativa has long been used for medicinal purposes.

To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids.

Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain.

More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection.

The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear.

In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects.

This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.”

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