The nephrologist’s guide to cannabis and cannabinoids.

“Cannabis (marijuana, weed, pot, ganja, Mary Jane) is the most commonly used federally illicit drug in the United States.

The present review provides an overview of cannabis and cannabinoids with relevance to the practice of nephrology so that clinicians can best take care of patients.

RECENT FINDINGS:

Cannabis may have medicinal benefits for treating symptoms of advanced chronic kidney disease (CKD) and end-stage renal disease including as a pain adjuvant potentially reducing the need for opioids.

Cannabis does not seem to affect kidney function in healthy individuals. However, renal function should be closely monitored in those with CKD, the lowest effective dose should be used, and smoking should be avoided. Cannabis use may delay transplant candidate listing or contribute to ineligibility.

Cannabidiol (CBD) has recently exploded in popularity. Although generally well tolerated, safe without significant side effects, and effective for a variety of neurological and psychiatric conditions, consumers have easy access to a wide range of unregulated CBD products, some with inaccurate labeling and false health claims. Importantly, CBD may raise tacrolimus levels.

SUMMARY:

Patients and healthcare professionals have little guidance or evidence regarding the impact of cannabis use on people with kidney disease. This knowledge gap will remain as long as federal regulations remain prohibitively restrictive towards prospective research.”

https://www.ncbi.nlm.nih.gov/pubmed/31972598

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Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review.

 Image result for bmc psychiatry“Medicinal cannabis has received increased research attention over recent years due to loosening global regulatory changes.

Medicinal cannabis has been reported to have potential efficacy in reducing pain, muscle spasticity, chemotherapy-induced nausea and vomiting, and intractable childhood epilepsy. Yet its potential application in the field of psychiatry is lesser known.

CONCLUSIONS:

There is currently encouraging, albeit embryonic, evidence for medicinal cannabis in the treatment of a range of psychiatric disorders. Supportive findings are emerging for some key isolates, however, clinicians need to be mindful of a range of prescriptive and occupational safety considerations, especially if initiating higher dose THC formulas.”

https://www.ncbi.nlm.nih.gov/pubmed/31948424

https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-019-2409-8

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Source of cannabinoids: what is available, what is used, and where does it come from?

John Libbey Eurotext“Cannabis sativa L. is an ancient medicinal plant wherefrom over 120 cannabinoids are extracted. In the past two decades, there has been increasing interest in the therapeutic potential of cannabis-based treatments for neurological disorders such as epilepsy, and there is now evidence for the medical use of cannabis and its effectiveness for a wide range of diseases.

Cannabinoid treatments for pain and spasticity in patients with multiple sclerosis (Nabiximols) have been approved in several countries. Cannabidiol (CBD), in contrast to tetra-hydro-cannabidiol (THC), is not a controlled substance in the European Union, and over the years there has been increasing use of CBD-enriched extracts and pure CBD for seizure disorders, particularly in children. No analytical controls are mandatory for CBD-based products and a pronounced variability in CBD concentrations in commercialized CBD oil preparations has been identified.

Randomized controlled trials of plant-derived CBD for treatment of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) have provided evidence of anti-seizure effects, and in June 2018, CBD was approved by the Food and Drug Administration as an add-on antiepileptic drug for patients two years of age and older with LGS or DS. Medical cannabis, with various ratios of CBD and THC and in different galenic preparations, is licensed in many European countries for several indications, and in July 2019, the European Medicines Agency also granted marketing authorisation for CBD in association with clobazam, for the treatment of seizures associated with LGS or DS.

The purpose of this article is to review the availability of cannabis-based products and cannabinoid-based medicines, together with current regulations regarding indications in Europe (as of July 2019). The lack of approval by the central agencies, as well as social and political influences, have led to significant variation in usage between countries.”

https://www.ncbi.nlm.nih.gov/pubmed/31941643

https://www.jle.com/fr/revues/epd/e-docs/source_of_cannabinoids_what_is_available_what_is_used_and_where_does_it_come_from__316043/article.phtml

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Therapeutic Uses of Cannabis on Sleep Disorders and Related Conditions.

 Related image“Marijuana generally refers to the dried mixture of leaves and flowers of the cannabis plant, and the term cannabis is a commonly used to refer to products derived from the Cannabis sativa L. plant. There has been an increasing interest in the potential medicinal use of cannabis to treat a variety of diseases and conditions. This review will provide the latest evidence regarding the medical risks and potential therapeutic benefits of cannabis in managing patients with sleep disorders or those with other medical conditions who commonly suffer with sleep disturbance as an associated comorbidity. Published data regarding the effects of cannabis compounds on sleep in the general population, as well as in patients with insomnia, chronic pain, posttraumatic stress disorder, and other neurological conditions, will be presented. Current trends for marijuana use and its effects on the economy and the implications that those trends and effects have on future research into medical cannabis are also presented.”

https://www.ncbi.nlm.nih.gov/pubmed/31895189

https://insights.ovid.com/crossref?an=00004691-202001000-00007

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A North American History of Cannabis Use in the Treatment of Epilepsy.

 Related image“Cannabis has been used for millennia in religious ceremonies, for recreation and for its medicinal qualities. There are multiple accounts detailing the specific ailments cannabis has been used to treat, many of which have included epilepsy. Racial discrimination and political stigmatization led to prohibition, which limited both patients’ and researchers’ access to the drug through the 20th century. Recently, academic interest has been renewed in cannabis, especially regarding the modulation of cortical excitability via the human endocannabinoid system. Modern research has produced several promising studies regarding the treatment of epileptic encephalopathies. Legalization of marijuana in Canada has potentially allowed for further trials, but it is by no means an end to the controversy surrounding the treatment of epilepsy with cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/31895188

https://insights.ovid.com/crossref?an=00004691-202001000-00006

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The Endocannabinoid System and Synthetic Cannabinoids in Preclinical Models of Seizure and Epilepsy.

 Related image“Cannabinoids are compounds that are structurally and/or functionally related to the primary psychoactive constituent of Cannabis sativa, [INCREMENT]-tetrahydrocannabinol (THC). Cannabinoids can be divided into three broad categories: endogenous cannabinoids, plant-derived cannabinoids, and synthetic cannabinoids (SCs).

Recently, there has been an unprecedented surge of interest into the pharmacological and medicinal properties of cannabinoids for the treatment of epilepsies. This surge has been stimulated by an ongoing shift in societal opinions about cannabinoid-based medicines and evidence that cannabidiol, a nonintoxicating plant cannabinoid, has demonstrable anticonvulsant activity in children with treatment-refractory epilepsy.

The major receptors of the endogenous cannabinoid system (ECS)-the type 1 and 2 cannabinoid receptors (CB1R, CB2R)-have critical roles in the modulation of neurotransmitter release and inflammation, respectively; so, it is not surprising therefore that the ECS is being considered as a target for the treatment of epilepsy.

SCs were developed as potential new drug candidates and tool compounds for studying the ECS. Beyond the plant cannabinoids, an extensive research effort is underway to determine whether SCs that directly target CB1R, CB2R, or the enzymes that breakdown endogenous cannabinoids have anticonvulsant effects in preclinical rodent models of epilepsy and seizure.

This research demonstrates that many SCs do reduce seizure severity in rodent models and may have both positive and negative pharmacodynamic and pharmacokinetic interactions with clinically used antiepilepsy drugs. Here, we provide a comprehensive review of the preclinical evidence for and against SC modulation of seizure and discuss the important questions that need to be addressed in future studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31895186

https://insights.ovid.com/crossref?an=00004691-202001000-00004

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Isolation of a High-Affinity Cannabinoid for the Human CB1 Receptor from a Medicinal Cannabis sativa Variety: Δ9-Tetrahydrocannabutol, the Butyl Homologue of Δ9-Tetrahydrocannabinol.

Go to Volume 0, Issue 0“The butyl homologues of Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabutol (Δ9-THCB), and cannabidiol, cannabidibutol (CBDB), were isolated from a medicinal Cannabis sativa variety (FM2) inflorescence. Appropriate spectroscopic and spectrometric characterization, including NMR, UV, IR, ECD, and HRMS, was carried out on both cannabinoids. The chemical structures and absolute configurations of the isolated cannabinoids were confirmed by comparison with the spectroscopic data of the respective compounds obtained by stereoselective synthesis. The butyl homologue of Δ9-THC, Δ9-THCB, showed an affinity for the human CB1 (Ki = 15 nM) and CB2 receptors (Ki = 51 nM) comparable to that of (-)-trans9-THC. Docking studies suggested the key bonds responsible for THC-like binding affinity for the CB1 receptor. The formalin test in vivo was performed on Δ9-THCB in order to reveal possible analgesic and anti-inflammatory properties. The tetrad test in mice showed a partial agonistic activity of Δ9-THCB toward the CB1 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/31891265

https://pubs.acs.org/doi/abs/10.1021/acs.jnatprod.9b00876

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Medicinal Use of Cannabis in Children and Pregnant Women.

 Image result for Rambam Maimonides Med J.“The increasing medicinal use of cannabis during recent years has largely overlooked children and pregnant women due to litigious and ethical concerns.

However, over the last few years medicine has observed increasing numbers of children treated with cannabis for autism spectrum disorder (ASD) and fetal alcohol spectrum disorder (FASD), and pregnant women treated for hyperemesis gravidarum (HG).

This review provides an account of major findings discovered through this research.

Specifically, cannabis may offer therapeutic advantages to behavioral symptoms of autism spectrum disorder and fetal alcohol spectrum disorder, and to the severe nausea and vomiting in hyperemesis gravidarum.

The use of medical cannabis in children and pregnant women should be further discussed and researched in this patient population.”

https://www.ncbi.nlm.nih.gov/pubmed/31826800

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Cannabis-based medicines and the perioperative physician.

Image result for perioperative medicine

“Cannabis use for medicinal purposes was first documented in 2900 BC in China, when Emperor Shen Nong described benefit for rheumatism and malaria and later in Ancient Egyptian texts.

Discussion in medical journals, the mainstream and social media around the use of cannabis for medicinal and non-medicinal purposes has increased recently, especially following the legalisation of cannabis for recreational use in Canada and the UK government’s decision to make cannabis-based medicines (CBMs) available for prescription by doctors on the specialist register.

The actual, social and economic legitimisation of cannabis and its medicinal derivatives makes it likely increasing numbers of patients will present on this class of medicines. Perioperative physicians will require a sound understanding of their pharmacology and evidence base, and may wish to exploit this group of compounds for therapeutic purposes in the perioperative period.

The increasing availability of cannabis for both recreational and medicinal purposes means that anaesthetists will encounter an increasing number of patients taking cannabis-based medications. The existing evidence base is conflicted and incomplete regarding the indications, interactions and long-term effects of these substances.

Globally, most doctors have had little education regarding the pharmacology of cannabis-based medicines, despite the endocannabinoid system being one of the most widespread in the human body.

Much is unknown, and much is to be decided, including clarifying definitions and nomenclature, and therapeutic indications and dosing. Anaesthetists, Intensivists, Pain and Perioperative physicians will want to contribute to this evidence base and attempt to harness such therapeutic benefits in terms of pain relief and opiate-avoidance, anti-emesis and seizure control.

We present a summary of the pharmacology of cannabis-based medicines including anaesthetic interactions and implications, to assist colleagues encountering these medicines in clinical practice.”

https://www.ncbi.nlm.nih.gov/pubmed/31827774

“In summary, cannabinoids may improve pain relief as part of multi-modal approach. As the evidence base increases, CBMs could become part of the perioperative teams’ armamentarium to help provide an opiate sparing multimodal analgesia regime as well as having a role in the management of common post-operative complications such as nausea and vomiting.”

 https://perioperativemedicinejournal.biomedcentral.com/articles/10.1186/s13741-019-0127-x
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Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo controlled, randomised clinical trial of efficacy and safety of cannabidiol (CBD).

 

Image result for bmc palliative care“Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids, but there is little high quality evidence to guide clinicians. This study aims to define the role of cannabidiol (CBD) in the management of symptom burden in patients with advanced cancer undergoing standard palliative care.

METHODS AND DESIGN:

This study is a multicentre, randomised, placebo controlled, two arm, parallel trial of escalating doses of oral CBD. It will compare efficacy and safety outcomes of a titrated dose of CBD (100 mg/mL formulation, dose range 50 mg to 600 mg per day) against placebo. There is a 2-week patient determined titration phase, using escalating doses of CBD or placebo to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians.

DISCUSSION:

A major strength of this study is that it will target symptom burden as a whole, rather than just individual symptoms, in an attempt to describe the general improvement in wellbeing previously reported by some patients in open label, non controlled trials of medicinal cannabis. Randomisation with placebo is essential because of the well-documented over reporting of benefit in uncontrolled trials and high placebo response rates in cancer pain trials. This will be the first placebo controlled clinical trial to evaluate rigorously the efficacy, safety and acceptability of CBD for symptom relief in advanced cancer patients. This study will provide the medical community with evidence to present to patients wishing to access medicinal cannabis for their cancer related symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/31810437

https://bmcpalliatcare.biomedcentral.com/articles/10.1186/s12904-019-0494-6

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