Medical cannabis: considerations for the anesthesiologist and pain physician.

“New regulations are in place at the federal and provincial levels in Canada regarding the way medical cannabis is to be controlled. We present them together with guidance for the safe use of medical cannabis and recent clinical trials on cannabis and pain.

Health Canada has approved a new regulation on medical marijuana/cannabis, the Marihuana for Medical Purposes Regulations: The production of medical cannabis by individuals is illegal. Health Canada, however, has licensed authorized producers across the country, limiting the production to specific licenses of certain cannabis products. There are currently 26 authorized licensed producers from seven Canadian provinces offering more than 200 strains of marijuana.

We provide guidance for the safe use of medical cannabis.

The recent literature indicates that currently available cannabinoids are modestly effective analgesics that provide a safe, reasonable therapeutic option for managing chronic non-cancer-related pain.

The science of medical cannabis and the need for education of healthcare professionals and patients require continued effort. Although cannabinoids work to decrease pain, there is still a need to confirm these beneficial effects clinically and to exploit them with acceptable benefit-to-risk ratios.”

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Cannabidiol, neuroprotection and neuropsychiatric disorders.

“Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa.

It has possible therapeutic effects over a broad range of neuropsychiatric disorders.

CBD attenuates brain damage associated with neurodegenerative and/or ischemic conditions.

It also has positive effects on attenuating psychotic-, anxiety- and depressive-like behaviors.

Moreover, CBD affects synaptic plasticity and facilitates neurogenesis.

The mechanisms of these effects are still not entirely clear but seem to involve multiple pharmacological targets.

In the present review, we summarized the main biochemical and molecular mechanisms that have been associated with the therapeutic effects of CBD, focusing on their relevance to brain function, neuroprotection and neuropsychiatric disorders.”

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Medical marijuana programs – Why might they matter for public health and why should we better understand their impacts?

“Although cannabis is an illegal drug, ‘medical marijuana programs’ (MMPs) have proliferated (e.g., in Canada and several US states), allowing for legal cannabis use for therapeutic purposes.

While both health risks and potential therapeutic  for cannabis use have been documented, potential public health impacts of MMPs – also vis-à-vis other psychoactive substance use – remain under-explored.

We briefly reviewed the emerging evidence on MMP participants’ health status, and specifically other psychoactive substance use behaviors and outcomes.

MMP participants report improvements in overall health status, and specifically reductions in levels of risky alcohol, prescription drug and – to some extent – tobacco or other illicit drug use…”

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Medicinal cannabis.

“A number of therapeutic uses of cannabis and its derivatives have been postulated from preclinical investigations.

Possible clinical indications include spasticity and pain in multiple sclerosis, cancer-associated nausea and vomiting, cancer pain and HIV neuropathy.

Controversies lie in how to produce, supply and administer cannabinoid products.

Introduction of cannabinoids therapeutically should be supported by a regulatory and educational framework that minimises the risk of harm to patients and the community.

The Regulator of Medicinal Cannabis Bill 2014 is under consideration in Australia to address this.

Nabiximols is the only cannabinoid on the Australian Register of Therapeutic Goods at present, although cannabidiol has been recommended for inclusion in Schedule 4.”

“There is some evidence of therapeutic benefit for cannabis products in defined patient populations.”
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A systematic review of plant-derived natural compounds for anxiety disorders.

“Anxiety disorders are the most common mental illnesses affecting human beings. They range from panic to generalized anxiety disorders upsetting the well-being and psychosocial performance of patients. Several conventional anxiolytic drugs are being used which in turn result in several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being conducted by researchers.

The aim of the present study is to comprehensively review phytochemical compounds with well-established anxiolytic activities and their structure-activity relationships as well as neuropsychopharmacological aspects. Results showed that phytochemicals like; alkaloids, flavonoids, phenolic acids, lignans, cinnamates, terpenes and saponins possess anxiolytic effects in a wide range of animal models of anxiety.

The involved mechanisms include interaction with γ-aminobutyric acid (GABA)A receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine (5-HT)1A and 5-HT2A/C receptors, noradrenergic and dopaminergic systems, glycine and glutamate receptors, and κ-opioid receptor as well as cannabinoid (CB)1 and CB2 receptors.

Phytochemicals also modulate the hypothalamo-pituitary-adrenal (HPA) axis, the levels of pro-inflammatory cytokines like interleukin (IL)-2, IL-6, IL-1β and tumor necrosis factor (TNF)-α, and improve brain derived neurotrophic factor (BDNF) levels. Transient receptor potential cation channel subfamily V (TRPV)3, nitric oxide cyclic guanosine monophosphate (NO-cGMP) pathway and monoamine oxidase enzymes are other targets of phytochemicals with anxiolytic activity.

Taking together, these phytochemicals may be considered as supplements to conventional anxiolytic therapies in order to improve efficacy and reduce adverse effects.

Further preclinical and clinical studies are still needed in order to recognize the structure-activity relationships, metabolism, absorption, and neuropsychopharmacological mechanisms of plant-derived natural agents.”

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Cannabinoids for the Treatment of Schizophrenia: An Overview.

“Δ9-tetrahydrocannabinol and its analogues are found to have particular application in psychiatry because of their antipsychotic properties suggesting a therapeutic use as neuroleptic agents in limiting psychotic diseases.

These treatments should not only aim to alleviate specific symptoms but also attempt to delay/arrest disease progression.

In the present review, we reported recent studies supporting the view that the cannabinoid signalling system is a key modulatory element in the activity of the striatum and temporal cortex that has been traditionally associated with psychosis and schizophrenia.

This idea is supported by different anatomical, electrophysiological, pharmacological and biochemical data.

Furthermore, these studies indicate that the cannabinoid system is impaired in different psychotic disorders, supporting the idea of developing novel pharmacotherapies with compounds that selectively target specific elements of the cannabinoid system.”

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The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone-Induced Central Nervous System Demyelination.

“Different types of insults to the CNS lead to axon demyelination. Remyelination occurs when the CNS attempts to recover from myelin loss and requires the activation of oligodendrocyte precursor cells.

With the rationale that CB1 receptor is expressed in oligodendrocytes and marijuana consumption alters CNS myelination, we study the effects of the cannabinoid agonist WIN55212.2 in (1) an in vitro model of oligodendrocyte differentiation and (2) the cuprizone model for demyelination.

The cannabinoid agonist WIN55212.2 promotes oligodendrocyte differentiation in vitro.

Moreover, 0.5 mg/kg of the drug confers neuroprotection during cuprizone-induced demyelination, while 1 mg/kg aggravates the demyelination process.”

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JWH-133, a Selective Cannabinoid CB2 Receptor Agonist, Exerts Toxic Effects on Neuroblastoma SH-SY5Y Cells.

“Endocannabinoid system plays an important role in the regulation of diverse physiological functions.

Although cannabinoid type 2 receptors (CB2) are involved in the modulation of immune system in peripheral tissues, recent findings demonstrated that they are also expressed in the central nervous system and could constitute a new target for the treatment of neurodegenerative disorders.”

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Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveal a Mechanism for Regulation of Tumor Progression.

“The G-protein-coupled chemokine receptor, CXCR4, generates signals that lead to cell migration, cell proliferation, and other survival mechanisms which result in the metastatic spread of primary tumor cells to distal organs.

Numerous studies have demonstrated that CXCR4 can form homodimers, or can heterodimerize with other GPCRs to form receptor complexes that can amplify or decrease the signaling capacity of each individual receptor.

Using biophysical and biochemical approaches, we found that CXCR4 can form an induced heterodimer with cannabinoid receptor 2 (CB2) in human breast and prostate cancer cells.

Simultaneous, agonist-dependent activation of CXCR4 and CB2 resulted in reduced CXCR4-mediated expression of phosphorylated ERK1/2, and ultimately, reduced cancer cell functions such as calcium mobilization and cellular chemotaxis.

Given that treatment with cannabinoids has been shown to reduce invasiveness of cancer cells, as well as CXCR4-mediated migration of immune cells, it is therefore plausible that CXCR4 signaling can be silenced through a physical heterodimeric association with CB2, thereby inhibiting subsequent functions of CXCR4.

Taken together, the data illustrates a mechanism by which the cannabinoid system can negatively modulate CXCR4 receptor function, and perhaps, tumor progression.”

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Cannabinoids for treatment of glaucoma.

“The purpose of this article is to review the current status of cannabis in the treatment of glaucoma, including the greater availability of marijuana in the USA.

The pharmacology of marijuana and its effect on intraocular pressure has not changed since the research in the 1970s and 1980s.

Marijuana is an effective ocular hypotensive agent.

However, cardiovascular and neurological effects are observed at the same dose, and may theoretically reduce the beneficial effect of lowering intraocular pressure by reducing ocular blood flow. The clinician must be cognizant of this potential in diagnosis, prognosis, and therapy.”

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