Monthly Archives: November 2017

Synthesis of Photoswitchable Δ9-Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling.

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Journal of the American Chemical Society

“The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nerv-ous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ9-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly-rectifying potassium channels, as well as adenylyl cyclase.”

https://www.ncbi.nlm.nih.gov/pubmed/29161035

http://pubs.acs.org/doi/10.1021/jacs.7b06456

Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings.

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European Journal of Pain

“Cannabinoids have a long record of recreational and medical use and become increasingly approved for pain therapy. This development is based on preclinical and human experimental research summarized in this review.

Cannabinoid CB1 receptors are widely expressed throughout the nociceptive system. Their activation by endogenous or exogenous cannabinoids modulates the release of neurotransmitters. This is reflected in antinociceptive effects of cannabinoids in preclinical models of inflammatory, cancer and neuropathic pain, and by nociceptive hypersensitivity of cannabinoid receptor-deficient mice.

Cannabis-based medications available for humans mainly comprise Δ9 -tetrahydrocannabinol (THC), cannabidiol (CBD) and nabilone.

During the last 10 years, six controlled studies assessing analgesic effects of cannabinoid-based drugs in human experimental settings were reported. An effect on nociceptive processing could be translated to the human setting in functional magnetic resonance imaging studies that pointed at a reduced connectivity within the pain matrix of the brain. However, cannabinoid-based drugs heterogeneously influenced the perception of experimentally induced pain including a reduction in only the affective but not the sensory perception of pain, only moderate analgesic effects, or occasional hyperalgesic effects. This extends to the clinical setting.

While controlled studies showed a lack of robust analgesic effects, cannabis was nearly always associated with analgesia in open-label or retrospective reports, possibly indicating an effect on well-being or mood, rather than on sensory pain. Thus, while preclinical evidence supports cannabinoid-based analgesics, human evidence presently provides only reluctant support for a broad clinical use of cannabinoid-based medications in pain therapy.

SIGNIFICANCE:

Cannabinoids consistently produced antinociceptive effects in preclinical models, whereas they heterogeneously influenced the perception of experimentally induced pain in humans and did not provide robust clinical analgesia, which jeopardizes the translation of preclinical research on cannabinoid-mediated antinociception into the human setting.”

https://www.ncbi.nlm.nih.gov/pubmed/29160600

http://onlinelibrary.wiley.com/doi/10.1002/ejp.1148/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+

Effects of chronic Δ9-tetrahydrocannabinol treatment on Rho/Rho-kinase signalization pathway in mouse brain.

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Saudi Pharmaceutical Journal

“Δ9-Tetrahydrocannabinol (Δ9-THC) shows its effects by activating cannabinoid receptors which are on some tissues and neurons. Cannabinoid systems have role on cell proliferation and development of neurons. Furthermore, it is interesting that cannabinoidsystem and rho/rho-kinase signalization pathway, which have important role on cell development and proliferation, may have role on neuron proliferation and development together. Thus, a study is planned to investigate rhoA and rho-kinase enzyme expressions and their activities in the brain of chronic Δ9-THC treated mice. One group of mice are treated with Δ9-THC once to see effects of acute treatment. Another group of mice are treated with Δ9-THC three times per day for one month. After this period, rhoA and rho-kinase enzyme expressions and their activities in mice brains are analyzed by ELISA method. Chronic administration of Δ9-THC decreased the expression of rhoA while acute treatment has no meaningful effect on it. Administration of Δ9-THC did not affect expression of rho-kinase on both chronic and acute treatment. Administration of Δ9-THC increased rho-kinase activity on both chronic and acute treatment, however, chronic treatment decreased its activity with respect to acute treatment. This study showed that chronic Δ9-THC treatment down-regulated rhoA expression and did not change the expression level of rho-kinase which is downstream effector of rhoA. However, it elevated the rho-kinase activity. Δ9-THC induced down-regulation of rhoA may cause elevation of cypin expression and may have benefit on cypin related diseases. Furthermore, use of rho-kinase inhibitors and Δ9-THC together can be useful on rho-kinase related diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/29158718
http://www.sciencedirect.com/science/article/pii/S1319016417301081?via%3Dihub

Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies.

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“Chemotherapy-induced neuropathic pain is a distressing and commonly occurring side effect of many commonly used chemotherapeutic agents, which in some cases may prevent cancer patients from being able to complete their treatment.

Cannabinoid based therapies have the potential to manage or even prevent pain associated with this syndrome.

Pre-clinical animal studies that investigate the modulation of the endocannabinoid system (endogenous cannabinoid pathway) are being conducted to better understand the mechanisms behind this phenomenon.

Five recent pre-clinical studies identified from Medline published between 2013 and 2016 were selected for review. All studies evaluated the effect of small-molecule agonists or antagonists on components of the endocannabinoid system in rats or mice, using cisplatin or paclitax-el-induced allodynia as a model of chemotherapy-induced neuropathic pain. Activation of the cannabinoid receptor-2 (CB-2) receptor by AM1710 blocked paclitaxel-induced mechanical and cold allodynia in one study.

Four studies investigating the activation of both cannabinoid receptor-1 (CB-1) and CB-2 receptors by dual-agonists (WIN55,21 and CP55,940), or by the introduction of inhibitors of endocannabinoid metabolisers (URB597, URB937, JZL184, and SA-57) showed reduction of chemotherapy-induced al-lodynia. In addition, their results suggest that anti-allodynic effects may also be mediated by additional receptors, including TRPV1 and 5-hydroxytryptamine (5-HT1A).

Pre-clinical studies demon-strate that the activation of endocannabinoid CB-1 or CB-2 receptors produces physiological effects in animal models, namely the reduction of chemotherapy-induced allodynia. These studies also provide in-sight into the biological mechanism behind the therapeutic utility of cannabis compounds in managing chemotherapy-induced neuropathic pain, and provide a basis for the conduct of future clinical studies in patients of this population.”

https://www.ncbi.nlm.nih.gov/pubmed/29156899
http://apm.amegroups.com/article/view/16320

Standardized Cannabis sativa extract attenuates tau and stathmin gene expression in the melanoma cell line.

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Iranian Journal of Basic Medical Sciences

“Metastasis is the main cause of death in patients with melanoma.

Cannabis-based medicines are effective adjunctive drugs in cancer patients.

Tau and Stathmin proteins are the key proteins in cancer metastasis. Here we have investigated the effect of a standardized Cannabis sativa extract on cell migration and Tau and Stathmin gene expression in the melanoma cell line.

RESULTS:

Tau and stathmin gene expression was significantly decreased compared to the control group. Cell migration was also significantly reduced compared to controls.

CONCLUSION:

C. sativa decreased tau and stathmin gene expression and cancer metastasis. The results may have some clinical relevance for the use of cannabis-based medicines in patients with metastatic melanoma.”

https://www.ncbi.nlm.nih.gov/pubmed/29147495

http://ijbms.mums.ac.ir/article_9398.html

Associations between medical cannabis and prescription opioid use in chronic pain patients: A preliminary cohort study.

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Image result for plos one

“Current levels and dangers of opioid use in the U.S. warrant the investigation of harm-reducing treatment alternatives.

PURPOSE:

A preliminary, historical, cohort study was used to examine the association between enrollment in the New Mexico Medical Cannabis Program (MCP) and opioid prescription use.

RESULTS:

By the end of the 21 month observation period, MCP enrollment was associated with 17.27 higher age- and gender-adjusted odds of ceasing opioid prescriptions (CI 1.89 to 157.36, p = 0.012), 5.12 higher odds of reducing daily prescription opioid dosages (CI 1.56 to 16.88, p = 0.007), and a 47 percentage point reduction in daily opioid dosages relative to a mean change of positive 10.4 percentage points in the comparison group (CI -90.68 to -3.59, p = 0.034). The monthly trend in opioid prescriptions over time was negative among MCP patients (-0.64mg IV morphine, CI -1.10 to -0.18, p = 0.008), but not statistically different from zero in the comparison group (0.18mg IV morphine, CI -0.02 to 0.39, p = 0.081). Survey responses indicated improvements in pain reduction, quality of life, social life, activity levels, and concentration, and few side effects from using cannabis one year after enrollment in the MCP (ps<0.001).

CONCLUSIONS:

The clinically and statistically significant evidence of an association between MCP enrollment and opioid prescription cessation and reductions and improved quality of life warrants further investigations on cannabis as a potential alternative to prescription opioids for treating chronic pain.” https://www.ncbi.nlm.nih.gov/pubmed/29145417

“In summary, if cannabis can serve as an alternative to prescription opioids for at least some patients, legislators and the medical community may want to consider medical cannabis programs as a potential tool for combating the current opioid epidemic.”   http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187795

“Study finds medical cannabis is effective at reducing opioid addiction”  http://news.unm.edu/news/study-finds-medical-cannabis-is-effective-at-reducing-opioid-addiction

Multiple sclerosis symptoms and spasticity management: new data.

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Future Medicine Logo

“Spasticity, perceived by patients as muscle rigidity and spasms, is a common symptom in multiple sclerosis (MS). It is associated with functional impairment that can exacerbate other MS symptoms and reduce quality of life.

Pharmacological treatment options are limited and frequently ineffective. Treatment adherence is a key issue to address in these patients.

The efficacy and safety of 9-delta-tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray for treatment of MS spasticity were demonstrated in four Phase III trials.

Observational studies and registry data subsequently confirmed the effectiveness and tolerability of THC:CBD oromucosal spray under everyday practice conditions.

Among patients who respond to treatment, THC:CBD oromucosal spray has been shown to produce positive improvements in gait parameters and to normalize muscle fibers.”

https://www.ncbi.nlm.nih.gov/pubmed/29143581
https://www.futuremedicine.com/doi/10.2217/nmt-2017-0034

Study finds medical cannabis is effective at reducing opioid addiction

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Image result for university of new mexico

“A new study conducted by researchers at The University of New Mexico, involving medical cannabis and prescription opioid use among chronic pain patients, found a distinct connection between having the legal ability to use cannabis and significant reductions in opioid use.

The study titled, “Associations between Medical Cannabis and Prescription Opioid Use in Chronic Pain Patients: A Preliminary Cohort Study,” and published in the open access journal PLOS ONE, was conducted by Drs. Jacob Miguel Vigil, associate professor, Department of Psychology and Sarah See Stith, assistant professor, Department of Economics.

The results from this preliminary study showed a strong correlation between enrollment in the New Mexico Medical Cannabis Program (MCP) and cessation or reduction of opioid use, and that whole, natural Cannabis sativa and extracts made from the plant may serve as an alternative to opioid-based medications for treating chronic pain.

“If cannabis can serve as an alternative to prescription opioids for at least some patients, legislators and the medical community may want to consider medical cannabis programs as a potential tool for combating the current opioid epidemic,””

http://news.unm.edu/news/study-finds-medical-cannabis-is-effective-at-reducing-opioid-addiction

“Associations between medical cannabis and prescription opioid use in chronic pain patients: A preliminary cohort study.” http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187795

Medical cannabis Q&A

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  • “1. What is medical cannabis?

The term “medical cannabis” is used to describe products derived from the whole cannabis plant or its extracts containing a variety of active cannabinoids and terpenes, which patients take for medical reasons, after interacting with and obtaining authorization from their health care practitioner.

  • 2. What are the main active ingredients?

The chemical ingredients of cannabis are called cannabinoids. The 2 main therapeutic ones are:

  •  A Tetrahydrocannabinol (THC) is a partial agonist of CB1 and CB2 receptors. It is psychoactive and produces the euphoric effect.
  •  B Cannabidiol (CBD) has a weak affinity for CB1 and CB2 receptors and appears to exert its activity by enhancing the positive effects of the body’s endogenous cannabinoids
 3. Why do patients take it?

Medical cannabis may be used to alleviate symptoms for a variety of conditions. It has most commonly been used in neuropathic pain and other chronic pain conditions. There is limited, but developing, clinical evidence surrounding its safety and efficacy, and it does not currently have an approved Health Canada indication.

  • 4. How do patients take it?

Cannabis can be smoked, vaporized, taken orally, sublingually, topically or rectally. Different routes of administration will result in different pharmacokinetic and pharmacodynamic properties of the drug.

  • 5. Is it possible to develop dependence on medical cannabis?

Yes, abrupt discontinuation after long-term use may result in withdrawal symptoms. Additionally, chronic use may result in psychological dependence.

  • 6. What is the difference between medical and recreational cannabis?

Patients taking cannabis for medical reasons generally use cannabinoids to alleviate symptoms while minimizing intoxication, whereas recreational users may be taking cannabis for euphoric effects. Medical cannabis is authorized by a prescriber who provides a medical document allowing individuals to obtain cannabis from a licensed producer or apply to Health Canada to grow their own, whereas recreational cannabis is currently obtained through illicit means.

  • 7. How can patients access cannabis for medical purposes?
  • 8. Does medical cannabis have a DIN?

Pharmacological cannabinoids such as Sativex (delta-9-tetrahydrocannabinol-cannabidiol) and Cesamet (nabilone) have been approved for specific indications by Health Canada, however, herbal medical cannabis has not gone through Health Canada’s drug review and approval process, nor does it have a Drug Identification Number (DIN) or Natural Product Number (NPN).

  • 9. Is medical cannabis covered through insurance?

Some insurance plans may cover medical cannabis. Check each patient’s individual plan for more details.

  • 10. What role can pharmacists play in medical cannabis?

Even though pharmacists are not dispensing medical cannabis at this time, it is important for them to understand how their patients may use and access medical cannabis in order to provide effective medication management. Pharmacists may provide counselling on areas such as contraindications, drug interactions, management of side effects, alternative therapies, potential addictive behaviour and appropriate use.

  • 11. Where can I find more information about medical cannabis?

You can find more information on Health Canada’s website:” https://www.canada.ca/en/health-canada/services/drugs-health-products/medical-use-marijuana/medical-use-marijuana.html

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661684/

Availability and approval of cannabis-based medicines for chronic pain management and palliative/supportive care in Europe: A survey of the status in the chapters of the European Pain Federation.

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European Journal of Pain

“There is considerable public and political interest in the use of cannabis products for medical purposes.

METHODS:

The task force of the European Pain Federation (EFIC) conducted a survey with its national chapters representatives on the status of approval of all types of cannabis-based medicines, the covering of costs and the availability of a position paper of a national medical association on the use of medical cannabis for chronic pain and for symptom control in palliative/supportive care.

RESULTS:

Thirty-one out of 37 contacted councillors responded. Plant-derived tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray is approved for spasticity in multiple sclerosis refractory to conventional treatment in 21 EFIC chapters. Plant-derived THC (dronabinol) is approved for some palliative care conditions in four EFIC chapters. Synthetic THC analogue (nabilone) is approved for chemotherapy-associated nausea and vomiting refractory to conventional treatment in four EFIC chapters’. Eight EFIC chapters’ countries have an exceptional and six chapters an expanded access programme for medical cannabis. German and Israeli pain societies recommend the use of cannabis-based medicines as third-line drug therapies for chronic pain within a multicomponent approach. Conversely, the German medical association and a team of finish experts and officials do not recommend the prescription of medical cannabis due to the lack of high-quality evidence of efficacy and the potential harms.

CONCLUSIONS:

There are marked differences between the countries represented in EFIC in the approval and availability of cannabis-based products for medical use. EFIC countries are encouraged to collaborate with the European Medicines Agency to publish a common document on cannabis-based medicines.

SIGNIFICANCE:

There are striking differences between European countries in the availability of plant-derived and synthetic cannabinoids and of medical cannabis for pain management and for symptom control in palliative care and in the covering of costs by health insurance companies or state social security systems.”

https://www.ncbi.nlm.nih.gov/pubmed/29134767

http://onlinelibrary.wiley.com/doi/10.1002/ejp.1147/abstract