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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Cannabinoids and spinal cord stimulation for the treatment of failed back surgery syndrome refractory pain

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“This study aimed to evaluate pain and its symptoms in patients with failed back surgery syndrome (FBSS) refractory to other therapies, treated with a combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), in association with spinal cord stimulation (SCS).

Results: Effective pain management as compared to baseline result was achieved in all the cases studied. The positive effect of cannabinoid agonists on refractory pain was maintained during the entire duration of treatment with minimal dosage titration. Pain perception, evaluated through numeric rating scale, decreased from a baseline mean value of 8.18±1.07–4.72±0.9 by the end of the study duration (12 months) (P<0.001).

Conclusion: The results indicate that cannabinoid agonists (THC/CBD) can have remarkable analgesic capabilities, as adjuvant of SCS, for the treatment of chronic refractory pain of FBSS patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30233233

https://www.dovepress.com/cannabinoids-and-spinal-cord-stimulation-for-the-treatment-of-failed-b-peer-reviewed-article-JPR

“Outcomes indicate remarkable analgesic capabilities of cannabinoid agonists (THC/CBD) as an adjuvant to SCS for treating chronic refractory pain in FBSS patients, since all the cases studied achieved effective pain management compared to baseline.”

https://www.mdlinx.com/journal-summaries/cannabinoids-delta-9-tetrahydrocannabinol-thc-cannabidiol/2018/09/13/7544234/

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Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood.

Scientific Reports

“In summary, these results suggest that psychoactive cannabinoid exposure during adolescence is unlikely to have a major effect on the escalation of cocaine intake or the development of compulsive-like responding per se in adulthood in a rat model of cocaine self-administration.”

https://www.ncbi.nlm.nih.gov/pubmed/30224774

https://www.nature.com/articles/s41598-018-31921-5

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Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor.

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“Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer.

CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. Notably, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate acid receptor (NMDAR) activity and display positive effects on most of the aforesaid diseases. Thus, we investigated the effects of CBD on three animal models in which NMDAR overactivity plays a critical role: opioid analgesia attenuation, NMDA-induced convulsive syndrome and ischemic stroke.

In an in vitro assay, CBD disrupted the regulatory association of σ1R with the NR1 subunit of NMDAR, an effect shared by σ1R antagonists, such as BD1063 and progesterone, and prevented by σ1R agonists, such as 4-IBP, PPCC and PRE084. The in vivo administration of CBD or BD1063 enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion.

These positive effects of CBD were reduced by the σ1R agonists PRE084 and PPCC, and absent in σ1R-/- mice. Thus, CBD displays antagonist-like activity toward σ1R to reduce the negative effects of NMDAR overactivity in the abovementioned experimental situations.”

https://www.ncbi.nlm.nih.gov/pubmed/30223868

https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-018-0395-2

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Role of the endocannabinoid system in drug addiction.

Biochemical Pharmacology

“Drug addiction is a chronic relapsing disorder that produces a dramaticglobal health burden worldwide. Not effective treatment of drug addiction is currently available probably due to the difficulties to find an appropriate target to manage this complex disease raising the needs for further identification of novel therapeutic approaches.

The endocannabinoid system has been found to play a crucial role in the neurobiological substrate underlying drug addiction.

Endocannabinoids and cannabinoid receptors are widely expressed in the main areas of the mesocorticolimbic system that participate in the initiation and maintenance of drug consumption and in the development of compulsion and loss of behavioral control occurring during drug addiction.

The identification of the important role played by CB1 cannabinoid receptors in drug addiction encouraged the possible used of an early commercialized CB1 receptor antagonist for treating drug addiction.

However, the incidence of serious psychiatric adverse events leaded to the sudden withdrawal from the market of this CB1 antagonist and all the research programs developed by pharmaceutical companies to obtain new CB1 antagonists were stopped.

Currently, new research strategies are under development to target the endocannabinoid system for drug addiction avoiding these side effects, which include allosteric negative modulators of CB1 receptors and compounds targeting CB2 receptors.

Recent studies showing the potential role of CB2 receptors in the addictive properties of different drugs of abuse have open a promising research opportunity to develop novel possible therapeutic approaches.”

https://www.ncbi.nlm.nih.gov/pubmed/30217570

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303952

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False-positive cannabinoid screens in adult cystic fibrosis patients treated with lumacaftor/ivacaftor

Journal of Cystic Fibrosis

“Cystic fibrosis (CF) is caused by gene mutations resulting in defective cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. CFTR modulators have been developed to improve CFTR protein function. The combination of ivacaftor (IVA) and lumacaftor (LUM) partially restores CFTR protein function of F508del, the most common CF mutation.”

https://www.ncbi.nlm.nih.gov/pubmed/30217546

“False-positive cannabinoid screens in adult cystic fibrosis patients treated with lumacaftor/ivacaftor”

https://www.cysticfibrosisjournal.com/article/S1569-1993(18)30754-9/fulltext

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Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors.

Brain, Behavior, and Immunity

“The chronic use of drugs that reduce the dopaminergic neurotransmission can cause a hyperkinetic movement disorder called tardive dyskinesia (TD). The pathophysiology of this disorder is not entirely understood but could involve oxidative and neuroinflammatory mechanisms.

Cannabidiol (CBD), the major non-psychotomimetic compound present in Cannabis sativa plant, could be a possible therapeutic alternative for TD. This phytocannabinoid shows antioxidant, anti-inflammatory and antipsychotic properties and decreases the acute motor effects of classical antipsychotics.

The present study investigated if CBD would attenuate orofacial dyskinesia, oxidative stress and inflammatory changes induced by chronic administration of haloperidol in mice. Furthermore, we verified in vivo and in vitro (in primary microglial culture) whether these effects would be mediated by PPARγ receptors.

The results showed that the male Swiss mice treated daily for 21 days with haloperidol develop orofacial dyskinesia. Daily CBD administration before each haloperidol injection prevented this effect.

Mice treated with haloperidol showed an increase in microglial activation and inflammatory mediators in the striatum. These changes were also reduced by CBD. On the other hand, the levels of the anti-inflammatory cytokine IL-10 increased in the striatum of animals that received CBD and haloperidol.

Regarding oxidative stress, haloperidol induced lipid peroxidation and reduced catalase activity. This latter effect was attenuated by CBD. The combination of CBD and haloperidol also increased PGC-1α mRNA expression, a co-activator of PPARγ receptors. Pretreatment with the PPARγ antagonist, GW9662, blocked the behavioural effect of CBD in our TD model. CBD also prevented LPS-stimulated microglial activation, an effect that was also antagonized by GW9662.

In conclusion, our results suggest that CBD could prevent haloperidol-induced orofacial dyskinesia by activating PPARγ receptors and attenuating neuroinflammatory changes in the striatum.”

“Haloperidol, marketed under the trade name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndromemania in bipolar disorder, nausea and vomiting, delirium, agitation, acute psychosis, and hallucinations in alcohol withdrawal”  https://en.wikipedia.org/wiki/Haloperidol
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Inhibitory effects of cannabidiol on voltage-dependent sodium currents.

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“Cannabis sativa contains many related compounds known as phytocannabinoids. The main psychoactive and non-psychoactive compounds are Δ9-tetrahydrocannabidiol (THC) and cannabidiol (CBD), respectively.

Much of the evidence for clinical efficacy of CBD-mediated anti-epileptic effects has been from case reports or smaller surveys. The mechanisms for CBD’s anticonvulsant effects are unclear and likely involve non-cannabinoid receptor pathways.

CBD is reported to modulate several ion channels, including sodium channels (Nav). Evaluating therapeutic mechanisms and safety of CBD demands a richer understanding of its interactions with central nervous system targets. Here, we used voltage-clamp electrophysiology of HEK-293 cells and iPSC neurons to characterize the effects of CBD on Nav channels.

Our results show that CBD inhibits hNav1.1-1.7 currents, with an IC50 of 1.9-3.8 μM, suggesting that this inhibition could occur at therapeutically relevant concentrations. A steep Hill slope of ~3 suggested multiple interactions of CBD with Nav channels. CBD exhibited resting-state blockade, became more potent at depolarized potentials, and also slowed recovery from inactivation, supporting the idea that CBD binding preferentially stabilizes inactivated Nav channel states. We also found that CBD inhibits other voltage-dependent currents from diverse channels, including bacterial homomeric Nav channel (NaChBac) and voltage-gated potassium channel subunit Kv2.1. Lastly, the CBD block of Nav was temperature-dependent, with potency increasing at lower temperatures.

We conclude that CBD’s mode of action likely involves (1) compound partitioning in lipid membranes, which alters membrane fluidity affecting gating, and (2) undetermined direct interactions with sodium and potassium channels, whose combined effects are loss of channel excitability.”

https://www.ncbi.nlm.nih.gov/pubmed/30219789

http://www.jbc.org/content/early/2018/09/14/jbc.RA118.004929

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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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Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons Influences Microglial Activity.

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“Microglia, the resident immune cells of the brain, play important roles in defending the brain against pathogens and supporting neuronal circuit plasticity. Chronic or excessive pro-inflammatory responses of microglia damage neurons, therefore their activity is tightly regulated.

Pharmacological and genetic studies revealed that cannabinoid type 1 (CB1) receptor activity influences microglial activity, although microglial CB1 receptor expression is very low and activity-dependent. The CB1 receptor is mainly expressed on neurons in the central nervous system (CNS)-with an especially high level on GABAergic interneurons.

Here, we determined whether CB1 signaling on this neuronal cell type plays a role in regulating microglial activity.

Our result suggests that CB1 receptor agonists can modulate microglial activity indirectly, through CB1 receptors on GABAergic neurons.

Altogether, we demonstrated that GABAergic neurons, despite their relatively low density in the hippocampus, have a specific role in the regulation of microglial activity and cannabinoid signaling plays an important role in this arrangement.”

https://www.ncbi.nlm.nih.gov/pubmed/30210289

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00295/full

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