Cannabis in Pain Treatment: Clinical and Research Considerations

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“Cannabinoids show promise as therapeutic agents, particularly as analgesics, but their development and clinical use has been complicated by recognition of their botanical source, cannabis, as a substance of misuse.

Although research into endogenous cannabinoid systems and potential cannabinoid pharmaceuticals is slowly increasing, there has been intense societal interest in making herbal (plant) cannabis available for medicinal use; 23 U.S. States and all Canadian provinces currently permit use in some clinical contexts.

Whether or not individual professionals support the clinical use of herbal cannabis, all clinicians will encounter patients who elect to use it and therefore need to be prepared to advise them on cannabis-related clinical issues despite limited evidence to guide care.

Expanded research on cannabis is needed to better determine the individual and public health effects of increasing use of herbal cannabis and to advance understanding of the pharmaceutical potential of cannabinoids as medications.

This article reviews clinical, research, and policy issues related to herbal cannabis to support clinicians in thoughtfully advising and caring for patients who use cannabis, and it examines obstacles and opportunities to expand research on the health effects of herbal cannabis and cannabinoids.

Perspective

Herbal cannabis is increasingly available for clinical use in the United States despite continuing controversies over its efficacy and safety. This article explores important considerations in the use of plant Cannabis to better prepare clinicians to care for patients who use it, and identifies needed directions for research.”

http://www.jpain.org/article/S1526-5900%2816%2900543-5/fulltext

“APS Issues New Guidance on Medical Marijuana for Pain”  http://www.medscape.com/viewarticle/863396

Potentiation of cannabinoid-induced cytotoxicity in Mantle Cell Lymphoma through modulation of ceramide metabolism

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“Ceramide accumulation is a widely described event in cancers after various treatments.

Ceramide levels are elevated in Mantle Cell Lymphoma (MCL) cells following treatment with cannabinoids.

In previous publications we and others observed that induction of ceramide accumulation by cannabinoids leads to apoptosis in MCL, glioma and pancreatic cancer.

Here, we investigated the pathways of ceramide accumulation in the MCL cell line Rec-1 using the stable endocannabinoid analogue R(+)-methanandamide (R-MA).

Our findings suggest that R-MA induces cell death in MCL via CB1-mediated upregulation of the de novo ceramide synthesis pathway.

This is the first study showing that the cytotoxic effect of a cannabinoid can be enhanced by modulation of ceramide metabolism.

The results suggest that interference with ceramide conversion may provide a tool to enhance the targeted cell death-promoting effects of cannabinoids in MCL and other malignant lymphomas overexpressing the CB1 receptor.

Cannabinoids have been suggested as a new non-toxic therapeutic option for cancer treatment.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077284/

Cannabinoid receptors in mantle cell lymphoma

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“Mantle cell lymphoma (MCL) is a non-curable B cell lymphoma that in several independent studies have been shown to express higher levels of CB1 and CB2 than non-malignant B cells.

The endocannabinoid system is dysregulated in many types of cancer and is involved in the regulation of survival and proliferation of cancer cells and cancer stem cells, in cancer metabolism, as well as in pro-metastatic events such as angiogenesis, migration and invasion.

Previous in vitro studies of MCL cell lines and primary ex vivo isolated tumor cells have demonstrated that high concentrations of cannabinoid receptor ligands induced proliferation arrest and programmed cell death.

All together, the data suggest that perturbations in the endocannabinoid system participate in the regulation of multi-functional cell responses regarding proliferation, migration and cell death control.

Therefore, it can be concluded that further studies on pharmacological modulation of endocannabinoid accumulation and/or signaling offers an interesting option for novel anti-lymphoma therapy.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353235/

Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma.

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“We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB(1) and CB(2)).

In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated.

The present data suggest that targeting CB(1)/CB(2) may have therapeutic potential for the treatment of mantle cell lymphoma.”

http://www.ncbi.nlm.nih.gov/pubmed/16936228

Cannabinoid receptor ligands mediate growth inhibition and cell death in mantle cell lymphoma.

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“We have earlier reported overexpression of the central and peripheral cannabinoid receptors CB1 and CB2 in mantle cell lymphoma (MCL), a B cell non-Hodgkin lymphoma.

In this study, treatment with cannabinoid receptor ligands caused a decrease in viability of MCL cells, while control cells lacking CB1 were not affected.

Our data suggest that cannabinoid receptors may be considered as potential therapeutic targets in MCL.” http://www.ncbi.nlm.nih.gov/pubmed/16337199

“In conclusion, we have found that cannabinoid receptor ligands induce decreased viability, growth suppression and cell death by apoptosis in MCL cells, which express high levels of the CB1 receptor and moderate levels of CB2.

The current results in vitro suggest that CB1/CB2 ligands should be considered as agents for the treatment of MCL.”  http://onlinelibrary.wiley.com/doi/10.1016/j.febslet.2005.11.020/full

Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: growth inhibition by receptor activation.

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“Endogenous and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL).

In this study, we evaluated the expression of cannabinoid receptors type 1 and type 2 (CB1 and CB2) in non-Hodgkin lymphomas of B cell type.

Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing CB1 and CB2.”

http://www.ncbi.nlm.nih.gov/pubmed/18546271

The role of cannabinoid receptors and the endocannabinoid system in mantle cell lymphoma and other non-Hodgkin lymphomas.

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“The initiating oncogenic event in mantle cell lymphoma (MCL) is the translocation of cyclin D1, t(11;14)(q13;q32). However, other genetic aberrations are necessary for an overt lymphoma to arise. Like other B cell lymphomas, MCL at some points during the oncogenesis is dependent on interactions with other cells and factors in the microenvironment.

The G protein coupled receptors cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed at low levels on non-malignant lymphocytes and at higher levels in MCL and other lymphoma subtypes.

In this review we give an overview of what is known on the role of the cannabinoid receptors and their ligands in lymphoma as compared to non-malignant T and B lymphocytes.

In MCL cannabinoids mainly reduce cell proliferation and induce cell death.

Importantly, our recent findings demonstrate that cannabinoids may induce either apoptosis or another type of programmed cell death, cytoplasmic vacuolation/paraptosis in MCL.”

http://www.ncbi.nlm.nih.gov/pubmed/22024769

Characterization and antimicrobial activity of essential oils of industrial hemp varieties (Cannabis sativa L.).

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“The present study focused on inhibitory activity of freshly extracted essential oils from three legal (THC<0.2% w/v) hemp varieties (Carmagnola, Fibranova and Futura) on microbial growth.

The effect of different sowing times on oil composition and biological activity was also evaluated. Essential oils were distilled and then characterized through the gas chromatography and gas chromatography-mass spectrometry. Thereafter, the oils were compared to standard reagents on a broad range inhibition of microbial growth via minimum inhibitory concentration (MIC) assay. Microbial strains were divided into three groups: i) Gram (+) bacteria, which regard to food-borne pathogens or gastrointestinal bacteria, ii) Gram (-) bacteria and iii) yeasts, both being involved in plant interactions.

The results showed that essential oils of industrial hemp can significantly inhibit the microbial growth, to an extent depending on variety and sowing time.

It can be concluded that essential oils of industrial hemp, especially those of Futura, may have interesting applications to control spoilage and food-borne pathogens and phytopathogens microorganisms.”

http://www.ncbi.nlm.nih.gov/pubmed/19969046

Antimicrobial studies of the leaf of cannabis sativa L.

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“In vitro antimicrobial studies were conducted with aqueous, ethanolic and Petroleum ether extracts of the leaves of Cannabis sativa L. The acidic fraction was obtained from the ethanolic extract and 2% Sodium Hydroxide extract. Ethanolic extract, petroleum ether extract and the acidic fraction exhibited activity both against Gram-positive and Gram-negative bacteria and also against the fungi used in the study. The aqueous extract however, did not show any antimicrobial activity.”

http://www.ncbi.nlm.nih.gov/pubmed/16414764

Pain, Cannabis Species, and Cannabis Use Disorders.

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“The purpose of this study was to examine whether individuals who used medical cannabis for chronic pain were at increased risk for cannabis use problems compared with individuals who used medical cannabis for other reasons (e.g., anxiety, insomnia, and muscle spasms).

An additional aim was to determine whether individuals who used cannabis for chronic pain, as well as those who reported greater within-group pain levels, demonstrated a species preference (i.e., sativa, indica, hybrids) and the extent to which species preference was associated with cannabis use problems.

RESULTS:

Individuals who used cannabis to manage chronic pain experienced fewer cannabis use problems than those who did not use it for pain; among those who used it for pain, the average pain level in the past week was not associated with cannabis use problems. Furthermore, individuals who used cannabis for chronic pain were more likely to use indica over sativa. Preference for indica was associated with fewer cannabis use problems than preference for hybrid species.

CONCLUSIONS:

Individuals who use cannabis to manage chronic pain may be at a lower risk for cannabis use problems, relative to individuals who use it for other indications, potentially as a function of their species preference.”

http://www.ncbi.nlm.nih.gov/pubmed/27172585